CA3224064A1 - Capsaicin and trpv1 modulator compositions and methods of use thereof - Google Patents
Capsaicin and trpv1 modulator compositions and methods of use thereof Download PDFInfo
- Publication number
- CA3224064A1 CA3224064A1 CA3224064A CA3224064A CA3224064A1 CA 3224064 A1 CA3224064 A1 CA 3224064A1 CA 3224064 A CA3224064 A CA 3224064A CA 3224064 A CA3224064 A CA 3224064A CA 3224064 A1 CA3224064 A1 CA 3224064A1
- Authority
- CA
- Canada
- Prior art keywords
- day
- compound
- pharmaceutically acceptable
- acceptable salt
- virus
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 title claims abstract description 153
- 229960002504 capsaicin Drugs 0.000 title claims abstract description 73
- 235000017663 capsaicin Nutrition 0.000 title claims abstract description 73
- 239000000203 mixture Substances 0.000 title claims description 214
- 238000000034 method Methods 0.000 title claims description 108
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 116
- 201000010099 disease Diseases 0.000 claims abstract description 78
- 208000035475 disorder Diseases 0.000 claims abstract description 37
- 150000001875 compounds Chemical class 0.000 claims description 381
- 150000003839 salts Chemical class 0.000 claims description 318
- 239000012453 solvate Substances 0.000 claims description 243
- 230000000155 isotopic effect Effects 0.000 claims description 195
- 239000002207 metabolite Substances 0.000 claims description 193
- 239000008194 pharmaceutical composition Substances 0.000 claims description 127
- 125000000217 alkyl group Chemical group 0.000 claims description 86
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 78
- 239000000194 fatty acid Substances 0.000 claims description 77
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 75
- 229930195729 fatty acid Natural products 0.000 claims description 75
- 150000004665 fatty acids Chemical class 0.000 claims description 74
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 claims description 72
- 229910052739 hydrogen Inorganic materials 0.000 claims description 69
- 239000001257 hydrogen Substances 0.000 claims description 69
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 claims description 51
- 235000020673 eicosapentaenoic acid Nutrition 0.000 claims description 51
- 229960005135 eicosapentaenoic acid Drugs 0.000 claims description 51
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 claims description 51
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 49
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 49
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 49
- 239000005642 Oleic acid Substances 0.000 claims description 49
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 49
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 49
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 49
- 235000020669 docosahexaenoic acid Nutrition 0.000 claims description 37
- 239000003826 tablet Substances 0.000 claims description 37
- 229940090949 docosahexaenoic acid Drugs 0.000 claims description 36
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 claims description 35
- 229910052736 halogen Inorganic materials 0.000 claims description 34
- 150000002367 halogens Chemical class 0.000 claims description 32
- 208000027866 inflammatory disease Diseases 0.000 claims description 30
- 239000002775 capsule Substances 0.000 claims description 29
- 150000002431 hydrogen Chemical class 0.000 claims description 29
- 238000002347 injection Methods 0.000 claims description 26
- 239000007924 injection Substances 0.000 claims description 26
- 206010028980 Neoplasm Diseases 0.000 claims description 25
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- 238000001802 infusion Methods 0.000 claims description 24
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 claims description 22
- 235000020661 alpha-linolenic acid Nutrition 0.000 claims description 22
- 229960004488 linolenic acid Drugs 0.000 claims description 22
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 claims description 22
- 238000012384 transportation and delivery Methods 0.000 claims description 21
- 239000000725 suspension Substances 0.000 claims description 20
- 208000008589 Obesity Diseases 0.000 claims description 19
- 235000020824 obesity Nutrition 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 19
- 201000011510 cancer Diseases 0.000 claims description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 235000020660 omega-3 fatty acid Nutrition 0.000 claims description 17
- 206010012601 diabetes mellitus Diseases 0.000 claims description 15
- 229930003827 cannabinoid Natural products 0.000 claims description 14
- 239000003557 cannabinoid Substances 0.000 claims description 14
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 14
- 230000003405 preventing effect Effects 0.000 claims description 14
- 208000019022 Mood disease Diseases 0.000 claims description 13
- 239000000829 suppository Substances 0.000 claims description 13
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 claims description 12
- 229940012843 omega-3 fatty acid Drugs 0.000 claims description 12
- 230000002062 proliferating effect Effects 0.000 claims description 12
- 208000023275 Autoimmune disease Diseases 0.000 claims description 11
- LGEQQWMQCRIYKG-DOFZRALJSA-N anandamide Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)NCCO LGEQQWMQCRIYKG-DOFZRALJSA-N 0.000 claims description 10
- LGEQQWMQCRIYKG-UHFFFAOYSA-N arachidonic acid ethanolamide Natural products CCCCCC=CCC=CCC=CCC=CCCCC(=O)NCCO LGEQQWMQCRIYKG-UHFFFAOYSA-N 0.000 claims description 10
- XJQPQKLURWNAAH-UHFFFAOYSA-N dihydrocapsaicin Chemical compound COC1=CC(CNC(=O)CCCCCCC(C)C)=CC=C1O XJQPQKLURWNAAH-UHFFFAOYSA-N 0.000 claims description 10
- RBCYRZPENADQGZ-UHFFFAOYSA-N dihydrocapsaicin Natural products COC1=CC(COC(=O)CCCCCCC(C)C)=CC=C1O RBCYRZPENADQGZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000001990 intravenous administration Methods 0.000 claims description 9
- 239000007909 solid dosage form Substances 0.000 claims description 9
- 208000035143 Bacterial infection Diseases 0.000 claims description 8
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 8
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 8
- 238000007918 intramuscular administration Methods 0.000 claims description 8
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 8
- 238000007920 subcutaneous administration Methods 0.000 claims description 8
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 7
- 208000006454 hepatitis Diseases 0.000 claims description 7
- 231100000283 hepatitis Toxicity 0.000 claims description 7
- 238000002513 implantation Methods 0.000 claims description 7
- 230000004770 neurodegeneration Effects 0.000 claims description 7
- DPUOLQHDNGRHBS-UHFFFAOYSA-N Brassidinsaeure Natural products CCCCCCCCC=CCCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-UHFFFAOYSA-N 0.000 claims description 6
- URXZXNYJPAJJOQ-UHFFFAOYSA-N Erucic acid Natural products CCCCCCC=CCCCCCCCCCCCC(O)=O URXZXNYJPAJJOQ-UHFFFAOYSA-N 0.000 claims description 6
- DPUOLQHDNGRHBS-KTKRTIGZSA-N erucic acid Chemical compound CCCCCCCC\C=C/CCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-KTKRTIGZSA-N 0.000 claims description 6
- 238000002663 nebulization Methods 0.000 claims description 6
- 239000006200 vaporizer Substances 0.000 claims description 6
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 4
- 206010012289 Dementia Diseases 0.000 claims description 4
- 206010019280 Heart failures Diseases 0.000 claims description 4
- 208000006011 Stroke Diseases 0.000 claims description 4
- 208000029560 autism spectrum disease Diseases 0.000 claims description 4
- 208000020832 chronic kidney disease Diseases 0.000 claims description 4
- 201000000980 schizophrenia Diseases 0.000 claims description 4
- 230000037317 transdermal delivery Effects 0.000 claims description 4
- 108050004388 Transient receptor potential cation channel subfamily V member 1 Proteins 0.000 abstract description 72
- 235000002639 sodium chloride Nutrition 0.000 description 293
- 241000700605 Viruses Species 0.000 description 145
- 201000009030 Carcinoma Diseases 0.000 description 59
- 239000002552 dosage form Substances 0.000 description 54
- 230000000694 effects Effects 0.000 description 53
- 239000003814 drug Substances 0.000 description 45
- -1 (cyclohexyl)methyl Chemical group 0.000 description 41
- 210000004027 cell Anatomy 0.000 description 31
- 238000011282 treatment Methods 0.000 description 31
- 125000001424 substituent group Chemical group 0.000 description 30
- 229940124597 therapeutic agent Drugs 0.000 description 29
- 239000013589 supplement Substances 0.000 description 28
- 208000032839 leukemia Diseases 0.000 description 26
- 241000282414 Homo sapiens Species 0.000 description 25
- 206010039491 Sarcoma Diseases 0.000 description 23
- 239000003112 inhibitor Substances 0.000 description 23
- 125000003118 aryl group Chemical group 0.000 description 22
- 208000024891 symptom Diseases 0.000 description 22
- 239000005557 antagonist Substances 0.000 description 21
- 239000000546 pharmaceutical excipient Substances 0.000 description 21
- 108090000623 proteins and genes Proteins 0.000 description 20
- 230000007423 decrease Effects 0.000 description 19
- 125000001072 heteroaryl group Chemical group 0.000 description 19
- 239000003795 chemical substances by application Substances 0.000 description 18
- 238000009472 formulation Methods 0.000 description 18
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 18
- 102000004169 proteins and genes Human genes 0.000 description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
- 239000000126 substance Substances 0.000 description 16
- 102100029111 Fatty-acid amide hydrolase 1 Human genes 0.000 description 15
- 239000002253 acid Substances 0.000 description 15
- 125000000753 cycloalkyl group Chemical group 0.000 description 15
- 229940079593 drug Drugs 0.000 description 15
- 108010046094 fatty-acid amide hydrolase Proteins 0.000 description 15
- 230000037396 body weight Effects 0.000 description 14
- 230000002401 inhibitory effect Effects 0.000 description 13
- 235000018102 proteins Nutrition 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 12
- 239000000556 agonist Substances 0.000 description 12
- IYRMWMYZSQPJKC-UHFFFAOYSA-N kaempferol Chemical compound C1=CC(O)=CC=C1C1=C(O)C(=O)C2=C(O)C=C(O)C=C2O1 IYRMWMYZSQPJKC-UHFFFAOYSA-N 0.000 description 12
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 12
- 230000002438 mitochondrial effect Effects 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 108091006082 receptor inhibitors Proteins 0.000 description 12
- 241001529453 unidentified herpesvirus Species 0.000 description 12
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 11
- 241000282412 Homo Species 0.000 description 11
- 102000003566 TRPV1 Human genes 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 230000002265 prevention Effects 0.000 description 11
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 10
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 10
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 10
- 230000003247 decreasing effect Effects 0.000 description 10
- 239000008103 glucose Substances 0.000 description 10
- 208000015181 infectious disease Diseases 0.000 description 10
- 235000020778 linoleic acid Nutrition 0.000 description 10
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 10
- 239000004031 partial agonist Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- BXOCHUWSGYYSFW-HVWOQQCMSA-N spilanthol Chemical compound C\C=C\C=C/CC\C=C\C(=O)NCC(C)C BXOCHUWSGYYSFW-HVWOQQCMSA-N 0.000 description 10
- 239000003981 vehicle Substances 0.000 description 10
- 102000004190 Enzymes Human genes 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 210000000577 adipose tissue Anatomy 0.000 description 9
- 239000003940 fatty acid amidase inhibitor Substances 0.000 description 9
- 125000005842 heteroatom Chemical group 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 231100000682 maximum tolerated dose Toxicity 0.000 description 9
- 201000001441 melanoma Diseases 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 229940068196 placebo Drugs 0.000 description 9
- 239000000902 placebo Substances 0.000 description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 8
- PJAAESPGJOSQGZ-DZGBDDFRSA-N Isovelleral Chemical group O=CC1=C[C@@H]2CC(C)(C)C[C@@H]2[C@@]2(C)C[C@]21C=O PJAAESPGJOSQGZ-DZGBDDFRSA-N 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 8
- 229940126422 TRPV1 antagonist Drugs 0.000 description 8
- 239000011575 calcium Substances 0.000 description 8
- 229910052791 calcium Inorganic materials 0.000 description 8
- 239000000839 emulsion Substances 0.000 description 8
- 229940125425 inverse agonist Drugs 0.000 description 8
- 238000007911 parenteral administration Methods 0.000 description 8
- 208000035473 Communicable disease Diseases 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000013543 active substance Substances 0.000 description 7
- 239000000443 aerosol Substances 0.000 description 7
- 235000001014 amino acid Nutrition 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 7
- 239000003085 diluting agent Substances 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 238000013265 extended release Methods 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 229910052710 silicon Inorganic materials 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- UBSCDKPKWHYZNX-UHFFFAOYSA-N Demethoxycapillarisin Natural products C1=CC(O)=CC=C1OC1=CC(=O)C2=C(O)C=C(O)C=C2O1 UBSCDKPKWHYZNX-UHFFFAOYSA-N 0.000 description 6
- 241000196324 Embryophyta Species 0.000 description 6
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 6
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 6
- OPZKBPQVWDSATI-KHPPLWFESA-N N-Vanillyloleamide Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)NCC1=CC=C(O)C(OC)=C1 OPZKBPQVWDSATI-KHPPLWFESA-N 0.000 description 6
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 6
- 241001529934 Simian T-lymphotropic virus 3 Species 0.000 description 6
- 125000002947 alkylene group Chemical group 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 230000020411 cell activation Effects 0.000 description 6
- 229930003935 flavonoid Natural products 0.000 description 6
- 150000002215 flavonoids Chemical group 0.000 description 6
- 235000017173 flavonoids Nutrition 0.000 description 6
- 125000004474 heteroalkylene group Chemical group 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 235000008777 kaempferol Nutrition 0.000 description 6
- 239000002502 liposome Substances 0.000 description 6
- UXOUKMQIEVGVLY-UHFFFAOYSA-N morin Natural products OC1=CC(O)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UXOUKMQIEVGVLY-UHFFFAOYSA-N 0.000 description 6
- 230000036961 partial effect Effects 0.000 description 6
- CNVZJPUDSLNTQU-SEYXRHQNSA-N petroselinic acid Chemical compound CCCCCCCCCCC\C=C/CCCCC(O)=O CNVZJPUDSLNTQU-SEYXRHQNSA-N 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 5
- 241000283690 Bos taurus Species 0.000 description 5
- 235000008534 Capsicum annuum var annuum Nutrition 0.000 description 5
- 235000002568 Capsicum frutescens Nutrition 0.000 description 5
- 206010016654 Fibrosis Diseases 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 241000725303 Human immunodeficiency virus Species 0.000 description 5
- 206010025323 Lymphomas Diseases 0.000 description 5
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 5
- 241001505332 Polyomavirus sp. Species 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 208000027418 Wounds and injury Diseases 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 230000002411 adverse Effects 0.000 description 5
- BXOCHUWSGYYSFW-UHFFFAOYSA-N all-trans spilanthol Natural products CC=CC=CCCC=CC(=O)NCC(C)C BXOCHUWSGYYSFW-UHFFFAOYSA-N 0.000 description 5
- 125000000732 arylene group Chemical group 0.000 description 5
- 230000001363 autoimmune Effects 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000007859 condensation product Substances 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 239000002270 dispersing agent Substances 0.000 description 5
- 206010014599 encephalitis Diseases 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 230000004761 fibrosis Effects 0.000 description 5
- 230000037406 food intake Effects 0.000 description 5
- 125000005549 heteroarylene group Chemical group 0.000 description 5
- 125000006588 heterocycloalkylene group Chemical group 0.000 description 5
- 238000003364 immunohistochemistry Methods 0.000 description 5
- 208000014674 injury Diseases 0.000 description 5
- 230000003211 malignant effect Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000004005 microsphere Substances 0.000 description 5
- 210000002569 neuron Anatomy 0.000 description 5
- 230000007935 neutral effect Effects 0.000 description 5
- 230000007170 pathology Effects 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 230000000284 resting effect Effects 0.000 description 5
- 210000003491 skin Anatomy 0.000 description 5
- 210000004500 stellate cell Anatomy 0.000 description 5
- 239000000375 suspending agent Substances 0.000 description 5
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 5
- 239000000080 wetting agent Substances 0.000 description 5
- OGKKHZMANPWMSD-UHFFFAOYSA-N (2-amino-2-oxoethyl) n-[3-[5-(6-methoxynaphthalen-1-yl)-1,3-dioxan-2-yl]propyl]carbamate Chemical group C=1C=CC2=CC(OC)=CC=C2C=1C1COC(CCCNC(=O)OCC(N)=O)OC1 OGKKHZMANPWMSD-UHFFFAOYSA-N 0.000 description 4
- HLHYXXBCQOUTGK-FHCQLJOMSA-N (7R,14S)-dihydroxy-(4Z,8E,10E,12Z,16Z,19Z)-docosahexaenoic acid Chemical group CC\C=C/C\C=C/C[C@H](O)\C=C/C=C/C=C/[C@H](O)C\C=C/CCC(O)=O HLHYXXBCQOUTGK-FHCQLJOMSA-N 0.000 description 4
- 244000105624 Arachis hypogaea Species 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 241000271566 Aves Species 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 4
- 241000701022 Cytomegalovirus Species 0.000 description 4
- 241001466953 Echovirus Species 0.000 description 4
- 241000709661 Enterovirus Species 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- 241001663880 Gammaretrovirus Species 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 208000007465 Giant cell arteritis Diseases 0.000 description 4
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 241000712079 Measles morbillivirus Species 0.000 description 4
- 241000829388 Mus musculus polyomavirus 1 Species 0.000 description 4
- 241000125945 Protoparvovirus Species 0.000 description 4
- 241000702263 Reovirus sp. Species 0.000 description 4
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 4
- 208000024770 Thyroid neoplasm Diseases 0.000 description 4
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 4
- 101150016206 Trpv1 gene Proteins 0.000 description 4
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 208000006673 asthma Diseases 0.000 description 4
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 4
- 210000000481 breast Anatomy 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 230000002860 competitive effect Effects 0.000 description 4
- RRAFCDWBNXTKKO-UHFFFAOYSA-N eugenol Chemical compound COC1=CC(CC=C)=CC=C1O RRAFCDWBNXTKKO-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 235000019197 fats Nutrition 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical compound COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 4
- 239000007943 implant Substances 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 201000006747 infectious mononucleosis Diseases 0.000 description 4
- 210000003734 kidney Anatomy 0.000 description 4
- 239000007937 lozenge Substances 0.000 description 4
- 208000003747 lymphoid leukemia Diseases 0.000 description 4
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 4
- 230000002503 metabolic effect Effects 0.000 description 4
- 201000010879 mucinous adenocarcinoma Diseases 0.000 description 4
- RGOVYLWUIBMPGK-UHFFFAOYSA-N nonivamide Chemical compound CCCCCCCCC(=O)NCC1=CC=C(O)C(OC)=C1 RGOVYLWUIBMPGK-UHFFFAOYSA-N 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- OPZKBPQVWDSATI-UHFFFAOYSA-N oleoyl vanillylamide Natural products CCCCCCCCC=CCCCCCCCC(=O)NCC1=CC=C(O)C(OC)=C1 OPZKBPQVWDSATI-UHFFFAOYSA-N 0.000 description 4
- 239000004006 olive oil Substances 0.000 description 4
- 235000008390 olive oil Nutrition 0.000 description 4
- 229950010717 olvanil Drugs 0.000 description 4
- 235000020665 omega-6 fatty acid Nutrition 0.000 description 4
- 238000003305 oral gavage Methods 0.000 description 4
- 230000000704 physical effect Effects 0.000 description 4
- 230000000069 prophylactic effect Effects 0.000 description 4
- 230000002285 radioactive effect Effects 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 150000003384 small molecules Chemical class 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 210000003594 spinal ganglia Anatomy 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 238000013268 sustained release Methods 0.000 description 4
- 239000012730 sustained-release form Substances 0.000 description 4
- 238000012385 systemic delivery Methods 0.000 description 4
- 206010043207 temporal arteritis Diseases 0.000 description 4
- 230000004797 therapeutic response Effects 0.000 description 4
- 229910052722 tritium Inorganic materials 0.000 description 4
- OJYLAHXKWMRDGS-UHFFFAOYSA-N zingerone Chemical compound COC1=CC(CCC(C)=O)=CC=C1O OJYLAHXKWMRDGS-UHFFFAOYSA-N 0.000 description 4
- OXEDXHIBHVMDST-UHFFFAOYSA-N 12Z-octadecenoic acid Natural products CCCCCC=CCCCCCCCCCCC(O)=O OXEDXHIBHVMDST-UHFFFAOYSA-N 0.000 description 3
- SXGZJKUKBWWHRA-UHFFFAOYSA-N 2-(N-morpholiniumyl)ethanesulfonate Chemical compound [O-]S(=O)(=O)CC[NH+]1CCOCC1 SXGZJKUKBWWHRA-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 3
- 241001664176 Alpharetrovirus Species 0.000 description 3
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 3
- 208000009299 Benign Mucous Membrane Pemphigoid Diseases 0.000 description 3
- 241000145903 Bombyx mori cypovirus 1 Species 0.000 description 3
- 208000003170 Bronchiolo-Alveolar Adenocarcinoma Diseases 0.000 description 3
- 240000004160 Capsicum annuum Species 0.000 description 3
- 208000009458 Carcinoma in Situ Diseases 0.000 description 3
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 3
- 241000711573 Coronaviridae Species 0.000 description 3
- 108010001517 Galectin 3 Proteins 0.000 description 3
- 208000032612 Glial tumor Diseases 0.000 description 3
- 206010018338 Glioma Diseases 0.000 description 3
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 3
- 206010019708 Hepatic steatosis Diseases 0.000 description 3
- 241000238631 Hexapoda Species 0.000 description 3
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 3
- 241000598436 Human T-cell lymphotropic virus Species 0.000 description 3
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 3
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 3
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 3
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 3
- 206010061598 Immunodeficiency Diseases 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 3
- 208000034578 Multiple myelomas Diseases 0.000 description 3
- IKMDFBPHZNJCSN-UHFFFAOYSA-N Myricetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC(O)=C(O)C(O)=C1 IKMDFBPHZNJCSN-UHFFFAOYSA-N 0.000 description 3
- 206010029260 Neuroblastoma Diseases 0.000 description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 3
- 206010034277 Pemphigoid Diseases 0.000 description 3
- CNVZJPUDSLNTQU-UHFFFAOYSA-N Petroselaidic acid Natural products CCCCCCCCCCCC=CCCCCC(O)=O CNVZJPUDSLNTQU-UHFFFAOYSA-N 0.000 description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 description 3
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 description 3
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 description 3
- 229910006074 SO2NH2 Inorganic materials 0.000 description 3
- 208000000389 T-cell leukemia Diseases 0.000 description 3
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 241000710959 Venezuelan equine encephalitis virus Species 0.000 description 3
- 241000711975 Vesicular stomatitis virus Species 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 208000002552 acute disseminated encephalomyelitis Diseases 0.000 description 3
- 208000009956 adenocarcinoma Diseases 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- XADJWCRESPGUTB-UHFFFAOYSA-N apigenin Natural products C1=CC(O)=CC=C1C1=CC(=O)C2=CC(O)=C(O)C=C2O1 XADJWCRESPGUTB-UHFFFAOYSA-N 0.000 description 3
- KZNIFHPLKGYRTM-UHFFFAOYSA-N apigenin Chemical compound C1=CC(O)=CC=C1C1=CC(=O)C2=C(O)C=C(O)C=C2O1 KZNIFHPLKGYRTM-UHFFFAOYSA-N 0.000 description 3
- 235000008714 apigenin Nutrition 0.000 description 3
- 229940117893 apigenin Drugs 0.000 description 3
- 239000007900 aqueous suspension Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000001728 capsicum frutescens Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 208000006990 cholangiocarcinoma Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000011260 co-administration Methods 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 239000006184 cosolvent Substances 0.000 description 3
- 235000012343 cottonseed oil Nutrition 0.000 description 3
- 239000002385 cottonseed oil Substances 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 125000002993 cycloalkylene group Chemical group 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 239000003571 electronic cigarette Substances 0.000 description 3
- 230000003028 elevating effect Effects 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 208000005017 glioblastoma Diseases 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 229940057995 liquid paraffin Drugs 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- IQPNAANSBPBGFQ-UHFFFAOYSA-N luteolin Chemical compound C=1C(O)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(O)C(O)=C1 IQPNAANSBPBGFQ-UHFFFAOYSA-N 0.000 description 3
- LRDGATPGVJTWLJ-UHFFFAOYSA-N luteolin Natural products OC1=CC(O)=CC(C=2OC3=CC(O)=CC(O)=C3C(=O)C=2)=C1 LRDGATPGVJTWLJ-UHFFFAOYSA-N 0.000 description 3
- 235000009498 luteolin Nutrition 0.000 description 3
- 238000002595 magnetic resonance imaging Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000003094 microcapsule Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- 208000025113 myeloid leukemia Diseases 0.000 description 3
- PCOBUQBNVYZTBU-UHFFFAOYSA-N myricetin Natural products OC1=C(O)C(O)=CC(C=2OC3=CC(O)=C(O)C(O)=C3C(=O)C=2)=C1 PCOBUQBNVYZTBU-UHFFFAOYSA-N 0.000 description 3
- 235000007743 myricetin Nutrition 0.000 description 3
- 229940116852 myricetin Drugs 0.000 description 3
- 210000003739 neck Anatomy 0.000 description 3
- 208000008795 neuromyelitis optica Diseases 0.000 description 3
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 235000021315 omega 9 monounsaturated fatty acids Nutrition 0.000 description 3
- 238000007410 oral glucose tolerance test Methods 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 238000011321 prophylaxis Methods 0.000 description 3
- 229960004063 propylene glycol Drugs 0.000 description 3
- 235000005875 quercetin Nutrition 0.000 description 3
- 229960001285 quercetin Drugs 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 230000000241 respiratory effect Effects 0.000 description 3
- 201000000306 sarcoidosis Diseases 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 230000007863 steatosis Effects 0.000 description 3
- 231100000240 steatosis hepatitis Toxicity 0.000 description 3
- 230000008093 supporting effect Effects 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 3
- 201000002510 thyroid cancer Diseases 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- AQWHMKSIVLSRNY-UHFFFAOYSA-N trans-Octadec-5-ensaeure Natural products CCCCCCCCCCCCC=CCCCC(O)=O AQWHMKSIVLSRNY-UHFFFAOYSA-N 0.000 description 3
- 241001430294 unidentified retrovirus Species 0.000 description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 description 3
- 239000008158 vegetable oil Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- BTKHXNIRAYKGMN-KHPPLWFESA-N (z)-n-[[4-(2-aminoethoxy)-3-methoxyphenyl]methyl]octadec-9-enamide Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)NCC1=CC=C(OCCN)C(OC)=C1 BTKHXNIRAYKGMN-KHPPLWFESA-N 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- PCZMUTQYZKAXBW-KHPPLWFESA-N 2-(4-hydroxy-3-methoxyphenyl)-n-[(z)-octadec-9-enyl]acetamide Chemical compound CCCCCCCC\C=C/CCCCCCCCNC(=O)CC1=CC=C(O)C(OC)=C1 PCZMUTQYZKAXBW-KHPPLWFESA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- DVLFYONBTKHTER-UHFFFAOYSA-N 3-(N-morpholino)propanesulfonic acid Chemical compound OS(=O)(=O)CCCN1CCOCC1 DVLFYONBTKHTER-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- 235000006491 Acacia senegal Nutrition 0.000 description 2
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 2
- 208000026872 Addison Disease Diseases 0.000 description 2
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 2
- 206010052747 Adenocarcinoma pancreas Diseases 0.000 description 2
- 208000009746 Adult T-Cell Leukemia-Lymphoma Diseases 0.000 description 2
- 208000016683 Adult T-cell leukemia/lymphoma Diseases 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 208000003829 American Hemorrhagic Fever Diseases 0.000 description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 2
- 235000003911 Arachis Nutrition 0.000 description 2
- 201000009695 Argentine hemorrhagic fever Diseases 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000031212 Autoimmune polyendocrinopathy Diseases 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 208000009137 Behcet syndrome Diseases 0.000 description 2
- 241001231757 Betaretrovirus Species 0.000 description 2
- 241000829192 Bos taurus polyomavirus 1 Species 0.000 description 2
- 241000701083 Bovine alphaherpesvirus 1 Species 0.000 description 2
- 241000700585 Bovine alphaherpesvirus 2 Species 0.000 description 2
- 241000710780 Bovine viral diarrhea virus 1 Species 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 206010058354 Bronchioloalveolar carcinoma Diseases 0.000 description 2
- 208000011691 Burkitt lymphomas Diseases 0.000 description 2
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 2
- 235000007862 Capsicum baccatum Nutrition 0.000 description 2
- 240000008574 Capsicum frutescens Species 0.000 description 2
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 2
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 2
- NPBVQXIMTZKSBA-UHFFFAOYSA-N Chavibetol Natural products COC1=CC=C(CC=C)C=C1O NPBVQXIMTZKSBA-UHFFFAOYSA-N 0.000 description 2
- 206010008583 Chloroma Diseases 0.000 description 2
- 208000006332 Choriocarcinoma Diseases 0.000 description 2
- 208000030939 Chronic inflammatory demyelinating polyneuropathy Diseases 0.000 description 2
- 241000710777 Classical swine fever virus Species 0.000 description 2
- 208000015943 Coeliac disease Diseases 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- 241000702421 Dependoparvovirus Species 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- 208000021866 Dressler syndrome Diseases 0.000 description 2
- 241000710945 Eastern equine encephalitis virus Species 0.000 description 2
- 241001115402 Ebolavirus Species 0.000 description 2
- 241000725630 Ectromelia virus Species 0.000 description 2
- 241000701081 Equid alphaherpesvirus 1 Species 0.000 description 2
- 241000701089 Equid alphaherpesvirus 4 Species 0.000 description 2
- 241000283073 Equus caballus Species 0.000 description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 2
- 239000005770 Eugenol Substances 0.000 description 2
- 241000701087 Felid alphaherpesvirus 1 Species 0.000 description 2
- 201000008808 Fibrosarcoma Diseases 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- 102100039558 Galectin-3 Human genes 0.000 description 2
- 241000608297 Getah virus Species 0.000 description 2
- 206010018364 Glomerulonephritis Diseases 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 241000150562 Hantaan orthohantavirus Species 0.000 description 2
- 241000893570 Hendra henipavirus Species 0.000 description 2
- 241000724709 Hepatitis delta virus Species 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 2
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 2
- 241001502974 Human gammaherpesvirus 8 Species 0.000 description 2
- 241000702617 Human parvovirus B19 Species 0.000 description 2
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 2
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 2
- 206010053574 Immunoblastic lymphoma Diseases 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 208000005615 Interstitial Cystitis Diseases 0.000 description 2
- 241000701460 JC polyomavirus Species 0.000 description 2
- 208000003456 Juvenile Arthritis Diseases 0.000 description 2
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 2
- 241000701646 Kappapapillomavirus 2 Species 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 208000012309 Linear IgA disease Diseases 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 2
- 241001480512 Mammalian orthoreovirus 3 Species 0.000 description 2
- 241001115401 Marburgvirus Species 0.000 description 2
- 208000037196 Medullary thyroid carcinoma Diseases 0.000 description 2
- 241000710185 Mengo virus Species 0.000 description 2
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 2
- 241000701029 Murid betaherpesvirus 1 Species 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 241000711466 Murine hepatitis virus Species 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- QVLMCRFQGHWOPM-ZKWNWVNESA-N N-arachidonoyl vanillylamine Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)NCC1=CC=C(O)C(OC)=C1 QVLMCRFQGHWOPM-ZKWNWVNESA-N 0.000 description 2
- 241000700635 Orf virus Species 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 241001631646 Papillomaviridae Species 0.000 description 2
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 2
- 208000000733 Paroxysmal Hemoglobinuria Diseases 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- 102100036050 Phosphatidylinositol N-acetylglucosaminyltransferase subunit A Human genes 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- 208000000474 Poliomyelitis Diseases 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- UVMRYBDEERADNV-UHFFFAOYSA-N Pseudoeugenol Natural products COC1=CC(C(C)=C)=CC=C1O UVMRYBDEERADNV-UHFFFAOYSA-N 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- 241000700564 Rabbit fibroma virus Species 0.000 description 2
- 241000320410 Rat sialodacryoadenitis coronavirus Species 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- 241000712909 Reticuloendotheliosis virus Species 0.000 description 2
- 201000001542 Schneiderian carcinoma Diseases 0.000 description 2
- 241001247145 Sebastes goodei Species 0.000 description 2
- 241000150278 Seoul orthohantavirus Species 0.000 description 2
- 241000700584 Simplexvirus Species 0.000 description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 206010042276 Subacute endocarditis Diseases 0.000 description 2
- 241000701093 Suid alphaherpesvirus 1 Species 0.000 description 2
- 206010042971 T-cell lymphoma Diseases 0.000 description 2
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 208000033781 Thyroid carcinoma Diseases 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 208000025851 Undifferentiated connective tissue disease Diseases 0.000 description 2
- 208000017379 Undifferentiated connective tissue syndrome Diseases 0.000 description 2
- 206010046851 Uveitis Diseases 0.000 description 2
- 241000700618 Vaccinia virus Species 0.000 description 2
- 241000700647 Variola virus Species 0.000 description 2
- 206010047115 Vasculitis Diseases 0.000 description 2
- 206010047642 Vitiligo Diseases 0.000 description 2
- 241000710951 Western equine encephalitis virus Species 0.000 description 2
- 241001536558 Yaba monkey tumor virus Species 0.000 description 2
- PNDPGZBMCMUPRI-XXSWNUTMSA-N [125I][125I] Chemical compound [125I][125I] PNDPGZBMCMUPRI-XXSWNUTMSA-N 0.000 description 2
- 230000001594 aberrant effect Effects 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 208000036676 acute undifferentiated leukemia Diseases 0.000 description 2
- 238000011374 additional therapy Methods 0.000 description 2
- 208000002517 adenoid cystic carcinoma Diseases 0.000 description 2
- 229960005305 adenosine Drugs 0.000 description 2
- 230000009418 agronomic effect Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 230000036528 appetite Effects 0.000 description 2
- 235000019789 appetite Nutrition 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 208000027625 autoimmune inner ear disease Diseases 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000007975 buffered saline Substances 0.000 description 2
- 208000000594 bullous pemphigoid Diseases 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 238000007707 calorimetry Methods 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 201000005795 chronic inflammatory demyelinating polyneuritis Diseases 0.000 description 2
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 201000010897 colon adenocarcinoma Diseases 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 230000037011 constitutive activity Effects 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 201000010549 croup Diseases 0.000 description 2
- 208000030381 cutaneous melanoma Diseases 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 208000037765 diseases and disorders Diseases 0.000 description 2
- 230000009429 distress Effects 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 201000002491 encephalomyelitis Diseases 0.000 description 2
- 201000004101 esophageal cancer Diseases 0.000 description 2
- 201000005619 esophageal carcinoma Diseases 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229960002217 eugenol Drugs 0.000 description 2
- 210000003527 eukaryotic cell Anatomy 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000012631 food intake Nutrition 0.000 description 2
- 235000021588 free fatty acids Nutrition 0.000 description 2
- 201000006585 gastric adenocarcinoma Diseases 0.000 description 2
- 235000002780 gingerol Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 229940075507 glyceryl monostearate Drugs 0.000 description 2
- 229960001867 guaiacol Drugs 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 239000007902 hard capsule Substances 0.000 description 2
- 210000003128 head Anatomy 0.000 description 2
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 2
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 201000004933 in situ carcinoma Diseases 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 238000007917 intracranial administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 208000024312 invasive carcinoma Diseases 0.000 description 2
- 229940044173 iodine-125 Drugs 0.000 description 2
- 235000015110 jellies Nutrition 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 201000005249 lung adenocarcinoma Diseases 0.000 description 2
- 201000005243 lung squamous cell carcinoma Diseases 0.000 description 2
- 206010025135 lupus erythematosus Diseases 0.000 description 2
- 208000025036 lymphosarcoma Diseases 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 239000011325 microbead Substances 0.000 description 2
- 235000013336 milk Nutrition 0.000 description 2
- 239000008267 milk Substances 0.000 description 2
- 210000004080 milk Anatomy 0.000 description 2
- 208000020298 milker nodule Diseases 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 201000006894 monocytic leukemia Diseases 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 206010028417 myasthenia gravis Diseases 0.000 description 2
- 201000005987 myeloid sarcoma Diseases 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000005445 natural material Substances 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 229960004036 nonivamide Drugs 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 231100000590 oncogenic Toxicity 0.000 description 2
- 230000002246 oncogenic effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000003973 paint Substances 0.000 description 2
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 201000003045 paroxysmal nocturnal hemoglobinuria Diseases 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- 235000020232 peanut Nutrition 0.000 description 2
- 229940116257 pepper extract Drugs 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 235000019100 piperine Nutrition 0.000 description 2
- WVWHRXVVAYXKDE-UHFFFAOYSA-N piperine Natural products O=C(C=CC=Cc1ccc2OCOc2c1)C3CCCCN3 WVWHRXVVAYXKDE-UHFFFAOYSA-N 0.000 description 2
- 208000031223 plasma cell leukemia Diseases 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 210000001236 prokaryotic cell Anatomy 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 208000002574 reactive arthritis Diseases 0.000 description 2
- 201000001281 rectum adenocarcinoma Diseases 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 201000003708 skin melanoma Diseases 0.000 description 2
- 208000000649 small cell carcinoma Diseases 0.000 description 2
- 235000015424 sodium Nutrition 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 208000008467 subacute bacterial endocarditis Diseases 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000011285 therapeutic regimen Methods 0.000 description 2
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 2
- 208000013818 thyroid gland medullary carcinoma Diseases 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 241000701366 unidentified nuclear polyhedrosis viruses Species 0.000 description 2
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 2
- 230000036642 wellbeing Effects 0.000 description 2
- DVSZKTAMJJTWFG-SKCDLICFSA-N (2e,4e,6e,8e,10e,12e)-docosa-2,4,6,8,10,12-hexaenoic acid Chemical compound CCCCCCCCC\C=C\C=C\C=C\C=C\C=C\C=C\C(O)=O DVSZKTAMJJTWFG-SKCDLICFSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- GZJLLYHBALOKEX-UHFFFAOYSA-N 6-Ketone, O18-Me-Ussuriedine Natural products CC=CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O GZJLLYHBALOKEX-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 230000035502 ADME Effects 0.000 description 1
- 241000714175 Abelson murine leukemia virus Species 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 208000032194 Acute haemorrhagic leukoencephalitis Diseases 0.000 description 1
- 206010000871 Acute monocytic leukaemia Diseases 0.000 description 1
- 241001428876 Adelaide River virus Species 0.000 description 1
- 241000321096 Adenoides Species 0.000 description 1
- 241000724685 African green monkey polyomavirus Species 0.000 description 1
- 241000120516 African horse sickness virus Species 0.000 description 1
- 241000701386 African swine fever virus Species 0.000 description 1
- 208000008190 Agammaglobulinemia Diseases 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 208000035805 Aleukaemic leukaemia Diseases 0.000 description 1
- 241001135972 Aleutian mink disease virus Species 0.000 description 1
- 208000032671 Allergic granulomatous angiitis Diseases 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 208000037540 Alveolar soft tissue sarcoma Diseases 0.000 description 1
- 241000190711 Amapari mammarenavirus Species 0.000 description 1
- 241000702419 Ambidensovirus Species 0.000 description 1
- 206010001935 American trypanosomiasis Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 208000028185 Angioedema Diseases 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 description 1
- 241000282709 Aotus trivirgatus Species 0.000 description 1
- 241000710189 Aphthovirus Species 0.000 description 1
- 241000702652 Aquareovirus Species 0.000 description 1
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- 241000712891 Arenavirus Species 0.000 description 1
- 206010003267 Arthritis reactive Diseases 0.000 description 1
- 241000701061 Ateline gammaherpesvirus 2 Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 241000178568 Aura virus Species 0.000 description 1
- 241000295638 Australian bat lyssavirus Species 0.000 description 1
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 1
- 206010071576 Autoimmune aplastic anaemia Diseases 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- 206010071577 Autoimmune hyperlipidaemia Diseases 0.000 description 1
- 206010069002 Autoimmune pancreatitis Diseases 0.000 description 1
- 208000022106 Autoimmune polyendocrinopathy type 2 Diseases 0.000 description 1
- 206010003840 Autonomic nervous system imbalance Diseases 0.000 description 1
- 241000701802 Aviadenovirus Species 0.000 description 1
- 241000711404 Avian avulavirus 1 Species 0.000 description 1
- 241000713840 Avian erythroblastosis virus Species 0.000 description 1
- 241000714230 Avian leukemia virus Species 0.000 description 1
- 241000713826 Avian leukosis virus Species 0.000 description 1
- 241000713838 Avian myeloblastosis virus Species 0.000 description 1
- 241000713842 Avian sarcoma virus Species 0.000 description 1
- 241000701397 Avihepadnavirus Species 0.000 description 1
- 241001651352 Avihepatovirus A Species 0.000 description 1
- 241000700663 Avipoxvirus Species 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 241000231314 Babanki virus Species 0.000 description 1
- 241000710946 Barmah Forest virus Species 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 208000023328 Basedow disease Diseases 0.000 description 1
- 241000608319 Bebaru virus Species 0.000 description 1
- 241001331006 Berrimah virus Species 0.000 description 1
- 241000405758 Betapartitivirus Species 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 241000150523 Black Creek Canal orthohantavirus Species 0.000 description 1
- 241000120506 Bluetongue virus Species 0.000 description 1
- 208000034200 Bolivian hemorrhagic fever Diseases 0.000 description 1
- 241001115070 Bornavirus Species 0.000 description 1
- 241000711443 Bovine coronavirus Species 0.000 description 1
- 241000712462 Bovine ephemeral fever virus Species 0.000 description 1
- 241001227615 Bovine foamy virus Species 0.000 description 1
- 241000713704 Bovine immunodeficiency virus Species 0.000 description 1
- 241000714266 Bovine leukemia virus Species 0.000 description 1
- 241000701822 Bovine papillomavirus Species 0.000 description 1
- 241000621124 Bovine papular stomatitis virus Species 0.000 description 1
- 241000701922 Bovine parvovirus Species 0.000 description 1
- 208000013165 Bowen disease Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 241000231316 Buggy Creek virus Species 0.000 description 1
- 241001493154 Bunyamwera virus Species 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 125000004406 C3-C8 cycloalkylene group Chemical group 0.000 description 1
- 241001493160 California encephalitis virus Species 0.000 description 1
- 241001137864 Camelpox virus Species 0.000 description 1
- 241000178270 Canarypox virus Species 0.000 description 1
- 241000680578 Canid alphaherpesvirus 1 Species 0.000 description 1
- 241000711506 Canine coronavirus Species 0.000 description 1
- 241000046998 Canine minute virus Species 0.000 description 1
- 241000712083 Canine morbillivirus Species 0.000 description 1
- 241000701931 Canine parvovirus Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 241000150506 Cano Delgadito orthohantavirus Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241000700664 Capripoxvirus Species 0.000 description 1
- 235000002566 Capsicum Nutrition 0.000 description 1
- 235000002283 Capsicum annuum var aviculare Nutrition 0.000 description 1
- 235000013303 Capsicum annuum var. frutescens Nutrition 0.000 description 1
- 235000002284 Capsicum baccatum var baccatum Nutrition 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 241000710190 Cardiovirus Species 0.000 description 1
- 241001181440 Carpias Species 0.000 description 1
- 208000005024 Castleman disease Diseases 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 241001467055 Caviid betaherpesvirus 2 Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241000701071 Cercopithecine alphaherpesvirus 2 Species 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 208000024699 Chagas disease Diseases 0.000 description 1
- 241000711969 Chandipura virus Species 0.000 description 1
- 241000120508 Changuinola virus Species 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 241001331000 Charleville virus Species 0.000 description 1
- 201000006082 Chickenpox Diseases 0.000 description 1
- 241001502567 Chikungunya virus Species 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 description 1
- 208000006344 Churg-Strauss Syndrome Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010009244 Claustrophobia Diseases 0.000 description 1
- 241000501789 Cocal virus Species 0.000 description 1
- 208000010007 Cogan syndrome Diseases 0.000 description 1
- 241000581522 Coho salmon aquareovirus Species 0.000 description 1
- 208000011038 Cold agglutinin disease Diseases 0.000 description 1
- 206010009868 Cold type haemolytic anaemia Diseases 0.000 description 1
- 241000204955 Colorado tick fever virus Species 0.000 description 1
- 241000702669 Coltivirus Species 0.000 description 1
- 208000013586 Complex regional pain syndrome type 1 Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000120509 Corriparta virus Species 0.000 description 1
- 241000700626 Cowpox virus Species 0.000 description 1
- 206010011258 Coxsackie myocarditis Diseases 0.000 description 1
- 241000709687 Coxsackievirus Species 0.000 description 1
- 241000710127 Cricket paralysis virus Species 0.000 description 1
- 241000150230 Crimean-Congo hemorrhagic fever orthonairovirus Species 0.000 description 1
- 206010011416 Croup infectious Diseases 0.000 description 1
- 208000019707 Cryoglobulinemic vasculitis Diseases 0.000 description 1
- 241000702662 Cypovirus Species 0.000 description 1
- 241001506928 Deformed wing virus Species 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 241000701809 Deltapapillomavirus 1 Species 0.000 description 1
- 241000701808 Deltapapillomavirus 2 Species 0.000 description 1
- 241001663879 Deltaretrovirus Species 0.000 description 1
- 241000725619 Dengue virus Species 0.000 description 1
- 206010012468 Dermatitis herpetiformis Diseases 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- 241000712471 Dhori virus Species 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 241000907524 Drosophila C virus Species 0.000 description 1
- 241000725618 Duck hepatitis B virus Species 0.000 description 1
- 241001176668 Duck hepatitis virus 2 Species 0.000 description 1
- 241001520695 Duvenhage lyssavirus Species 0.000 description 1
- 241000709643 Echovirus E9 Species 0.000 description 1
- 201000009051 Embryonal Carcinoma Diseases 0.000 description 1
- 241000710188 Encephalomyocarditis virus Species 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 206010057649 Endometrial sarcoma Diseases 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 206010014954 Eosinophilic fasciitis Diseases 0.000 description 1
- 208000018428 Eosinophilic granulomatosis with polyangiitis Diseases 0.000 description 1
- 206010014958 Eosinophilic leukaemia Diseases 0.000 description 1
- 206010064212 Eosinophilic oesophagitis Diseases 0.000 description 1
- 206010066919 Epidemic polyarthritis Diseases 0.000 description 1
- 241000120510 Epizootic hemorrhagic disease virus Species 0.000 description 1
- 241000725578 Equid gammaherpesvirus 2 Species 0.000 description 1
- 241001154301 Equine encephalosis virus Species 0.000 description 1
- 241000713730 Equine infectious anemia virus Species 0.000 description 1
- 206010015226 Erythema nodosum Diseases 0.000 description 1
- 208000032027 Essential Thrombocythemia Diseases 0.000 description 1
- 208000004332 Evans syndrome Diseases 0.000 description 1
- 241000465885 Everglades virus Species 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 208000001382 Experimental Melanoma Diseases 0.000 description 1
- 208000009331 Experimental Sarcoma Diseases 0.000 description 1
- 241000877986 Eyach virus Species 0.000 description 1
- 206010015958 Eye pain Diseases 0.000 description 1
- 201000006850 Familial medullary thyroid carcinoma Diseases 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 208000004729 Feline Leukemia Diseases 0.000 description 1
- 241000714201 Feline calicivirus Species 0.000 description 1
- 241000519954 Feline foamy virus Species 0.000 description 1
- 241000713800 Feline immunodeficiency virus Species 0.000 description 1
- 241000711475 Feline infectious peritonitis virus Species 0.000 description 1
- 241000714165 Feline leukemia virus Species 0.000 description 1
- 241000701915 Feline panleukopenia virus Species 0.000 description 1
- 241000701925 Feline parvovirus Species 0.000 description 1
- 241000714174 Feline sarcoma virus Species 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 241000711950 Filoviridae Species 0.000 description 1
- 241001470863 Flanders hapavirus Species 0.000 description 1
- 241000710831 Flavivirus Species 0.000 description 1
- 206010049238 Food aversion Diseases 0.000 description 1
- 241000710198 Foot-and-mouth disease virus Species 0.000 description 1
- 241000231322 Fort Morgan virus Species 0.000 description 1
- 241001428964 Four Corners hantavirus Species 0.000 description 1
- 241000701796 Fowl aviadenovirus 1 Species 0.000 description 1
- 241000700662 Fowlpox virus Species 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 241000531123 GB virus C Species 0.000 description 1
- 102000000802 Galectin 3 Human genes 0.000 description 1
- 241000701046 Gammaherpesvirinae Species 0.000 description 1
- 208000008999 Giant Cell Carcinoma Diseases 0.000 description 1
- 241000713813 Gibbon ape leukemia virus Species 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 241001112691 Goatpox virus Species 0.000 description 1
- 241001631709 Gonometa Species 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 241001517118 Goose parvovirus Species 0.000 description 1
- 208000003084 Graves Ophthalmopathy Diseases 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 241000700735 Ground squirrel hepatitis virus Species 0.000 description 1
- 241000190708 Guanarito mammarenavirus Species 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 206010061192 Haemorrhagic fever Diseases 0.000 description 1
- 206010019263 Heart block congenital Diseases 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 1
- 241000035314 Henipavirus Species 0.000 description 1
- 201000004331 Henoch-Schoenlein purpura Diseases 0.000 description 1
- 206010019617 Henoch-Schonlein purpura Diseases 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 241000724675 Hepatitis E virus Species 0.000 description 1
- 206010019771 Hepatitis F Diseases 0.000 description 1
- 208000037262 Hepatitis delta Diseases 0.000 description 1
- 241000709715 Hepatovirus Species 0.000 description 1
- 241000709721 Hepatovirus A Species 0.000 description 1
- 241001136039 Heron hepatitis B virus Species 0.000 description 1
- 206010019939 Herpes gestationis Diseases 0.000 description 1
- 208000029433 Herpesviridae infectious disease Diseases 0.000 description 1
- 241000710948 Highlands J virus Species 0.000 description 1
- 241000148627 Hirame novirhabdovirus Species 0.000 description 1
- 208000017662 Hodgkin disease lymphocyte depletion type stage unspecified Diseases 0.000 description 1
- 241000714259 Human T-lymphotropic virus 2 Species 0.000 description 1
- 241000701109 Human adenovirus 2 Species 0.000 description 1
- 241000713673 Human foamy virus Species 0.000 description 1
- 241001243761 Human hepatitis A virus Species 0.000 description 1
- 241000701027 Human herpesvirus 6 Species 0.000 description 1
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 1
- 241000701806 Human papillomavirus Species 0.000 description 1
- 241000829111 Human polyomavirus 1 Species 0.000 description 1
- 241000726041 Human respirovirus 1 Species 0.000 description 1
- 241000712003 Human respirovirus 3 Species 0.000 description 1
- 241001559187 Human rubulavirus 2 Species 0.000 description 1
- 241001559186 Human rubulavirus 4 Species 0.000 description 1
- 241001135958 Human type D retrovirus Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020843 Hyperthermia Diseases 0.000 description 1
- 206010020983 Hypogammaglobulinaemia Diseases 0.000 description 1
- 210000005131 Hürthle cell Anatomy 0.000 description 1
- 241000701378 Ichnovirus Species 0.000 description 1
- 241000700723 Ictalurid herpesvirus 1 Species 0.000 description 1
- 208000031814 IgA Vasculitis Diseases 0.000 description 1
- 208000010159 IgA glomerulonephritis Diseases 0.000 description 1
- 206010021263 IgA nephropathy Diseases 0.000 description 1
- 208000021330 IgG4-related disease Diseases 0.000 description 1
- 208000014919 IgG4-related retroperitoneal fibrosis Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 208000031781 Immunoglobulin G4 related sclerosing disease Diseases 0.000 description 1
- 208000004187 Immunoglobulin G4-Related Disease Diseases 0.000 description 1
- 241000711450 Infectious bronchitis virus Species 0.000 description 1
- 241000711804 Infectious hematopoietic necrosis virus Species 0.000 description 1
- 241000710921 Infectious pancreatic necrosis virus Species 0.000 description 1
- 241000712431 Influenza A virus Species 0.000 description 1
- 241001500351 Influenzavirus A Species 0.000 description 1
- 241001500350 Influenzavirus B Species 0.000 description 1
- 241001500343 Influenzavirus C Species 0.000 description 1
- 241000401052 Influenzavirus D Species 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 206010022524 Intentional self-injury Diseases 0.000 description 1
- 238000012695 Interfacial polymerization Methods 0.000 description 1
- 206010022557 Intermediate uveitis Diseases 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 241000701372 Iridovirus Species 0.000 description 1
- 241000710842 Japanese encephalitis virus Species 0.000 description 1
- 241000712890 Junin mammarenavirus Species 0.000 description 1
- 206010023256 Juvenile melanoma benign Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 241000120527 Kemerovo virus Species 0.000 description 1
- 241000897510 Klamath virus Species 0.000 description 1
- 241000479166 Kolongo virus Species 0.000 description 1
- 241000231318 Kyzylagach virus Species 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 241000713102 La Crosse virus Species 0.000 description 1
- 241000710789 Lactate dehydrogenase-elevating virus Species 0.000 description 1
- 201000010743 Lambert-Eaton myasthenic syndrome Diseases 0.000 description 1
- 241001428884 Langur virus Species 0.000 description 1
- 206010023927 Lassa fever Diseases 0.000 description 1
- 241000712902 Lassa mammarenavirus Species 0.000 description 1
- 206010024218 Lentigo maligna Diseases 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- 241000700563 Leporipoxvirus Species 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 206010053180 Leukaemia cutis Diseases 0.000 description 1
- 206010024305 Leukaemia monocytic Diseases 0.000 description 1
- 208000032514 Leukocytoclastic vasculitis Diseases 0.000 description 1
- 206010024434 Lichen sclerosus Diseases 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 241000609846 Lumpy skin disease virus Species 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 235000007688 Lycopersicon esculentum Nutrition 0.000 description 1
- 208000016604 Lyme disease Diseases 0.000 description 1
- 208000008771 Lymphadenopathy Diseases 0.000 description 1
- 241000701043 Lymphocryptovirus Species 0.000 description 1
- 241000712899 Lymphocytic choriomeningitis mammarenavirus Species 0.000 description 1
- 239000007993 MOPS buffer Substances 0.000 description 1
- 241000712898 Machupo mammarenavirus Species 0.000 description 1
- 241000218922 Magnoliophyta Species 0.000 description 1
- 241001480504 Mammalian orthoreovirus 1 Species 0.000 description 1
- 241001480506 Mammalian orthoreovirus 2 Species 0.000 description 1
- 241001559177 Mapuera rubulavirus Species 0.000 description 1
- 241000713821 Mason-Pfizer monkey virus Species 0.000 description 1
- 241000701244 Mastadenovirus Species 0.000 description 1
- 241000608292 Mayaro virus Species 0.000 description 1
- 208000007054 Medullary Carcinoma Diseases 0.000 description 1
- 208000009018 Medullary thyroid cancer Diseases 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 208000035490 Megakaryoblastic Acute Leukemia Diseases 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 241001643857 Menangle virus Species 0.000 description 1
- 208000027530 Meniere disease Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000710949 Middelburg virus Species 0.000 description 1
- 241000702625 Mink enteritis virus Species 0.000 description 1
- 241000702623 Minute virus of mice Species 0.000 description 1
- 208000003250 Mixed connective tissue disease Diseases 0.000 description 1
- 241000725171 Mokola lyssavirus Species 0.000 description 1
- 241000700559 Molluscipoxvirus Species 0.000 description 1
- 241000700560 Molluscum contagiosum virus Species 0.000 description 1
- 241000713862 Moloney murine sarcoma virus Species 0.000 description 1
- 241000700627 Monkeypox virus Species 0.000 description 1
- 208000035489 Monocytic Acute Leukemia Diseases 0.000 description 1
- 241000711513 Mononegavirales Species 0.000 description 1
- 208000024599 Mooren ulcer Diseases 0.000 description 1
- 241000712045 Morbillivirus Species 0.000 description 1
- 241000479161 Mount Elgon bat virus Species 0.000 description 1
- 241000713333 Mouse mammary tumor virus Species 0.000 description 1
- 241000868135 Mucambo virus Species 0.000 description 1
- 206010057269 Mucoepidermoid carcinoma Diseases 0.000 description 1
- 208000012192 Mucous membrane pemphigoid Diseases 0.000 description 1
- 206010073148 Multiple endocrine neoplasia type 2A Diseases 0.000 description 1
- 241000711386 Mumps virus Species 0.000 description 1
- 241001136036 Murid betaherpesvirus 2 Species 0.000 description 1
- 241000714177 Murine leukemia virus Species 0.000 description 1
- 241000711941 Murine orthopneumovirus Species 0.000 description 1
- 241000711408 Murine respirovirus Species 0.000 description 1
- 241000701034 Muromegalovirus Species 0.000 description 1
- 241000710908 Murray Valley encephalitis virus Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- 241000700562 Myxoma virus Species 0.000 description 1
- 241001457453 Nairobi sheep disease virus Species 0.000 description 1
- 241000264424 Nariva virus Species 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 241000238847 Nelson Bay orthoreovirus Species 0.000 description 1
- 206010071579 Neuronal neuropathy Diseases 0.000 description 1
- 241001244466 New world arenaviruses Species 0.000 description 1
- 241000526636 Nipah henipavirus Species 0.000 description 1
- 206010029488 Nodular melanoma Diseases 0.000 description 1
- 241000714209 Norwalk virus Species 0.000 description 1
- 241001428748 Ockelbo virus Species 0.000 description 1
- 241000277329 Oncorhynchus keta Species 0.000 description 1
- 208000003435 Optic Neuritis Diseases 0.000 description 1
- 241000702259 Orbivirus Species 0.000 description 1
- 241000250439 Oropouche virus Species 0.000 description 1
- 241000713112 Orthobunyavirus Species 0.000 description 1
- 241000150452 Orthohantavirus Species 0.000 description 1
- 241000700732 Orthohepadnavirus Species 0.000 description 1
- 241000150218 Orthonairovirus Species 0.000 description 1
- 241000700629 Orthopoxvirus Species 0.000 description 1
- 241000702244 Orthoreovirus Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000123724 Ovine papillomavirus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010053869 POEMS syndrome Diseases 0.000 description 1
- 241000120518 Palyam virus Species 0.000 description 1
- 241000282577 Pan troglodytes Species 0.000 description 1
- 241000057726 Panine gammaherpesvirus 1 Species 0.000 description 1
- 206010033701 Papillary thyroid cancer Diseases 0.000 description 1
- 241001504519 Papio ursinus Species 0.000 description 1
- 241001459566 Papulosa Species 0.000 description 1
- 206010048705 Paraneoplastic cerebellar degeneration Diseases 0.000 description 1
- 241000700639 Parapoxvirus Species 0.000 description 1
- 206010033976 Paravaccinia Diseases 0.000 description 1
- 208000004788 Pars Planitis Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 1
- 208000008223 Pemphigoid Gestationis Diseases 0.000 description 1
- 241000721454 Pemphigus Species 0.000 description 1
- 208000031845 Pernicious anaemia Diseases 0.000 description 1
- 244000025272 Persea americana Species 0.000 description 1
- 235000008673 Persea americana Nutrition 0.000 description 1
- 241000710778 Pestivirus Species 0.000 description 1
- 241000713137 Phlebovirus Species 0.000 description 1
- 241000711899 Phocine morbillivirus Species 0.000 description 1
- 241000709664 Picornaviridae Species 0.000 description 1
- 241000711965 Piry virus Species 0.000 description 1
- 208000000766 Pityriasis Lichenoides Diseases 0.000 description 1
- 206010048895 Pityriasis lichenoides et varioliformis acuta Diseases 0.000 description 1
- 241000868134 Pixuna virus Species 0.000 description 1
- 206010035742 Pneumonitis Diseases 0.000 description 1
- 241000711902 Pneumovirus Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 206010065159 Polychondritis Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 description 1
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 229920002582 Polyethylene Glycol 600 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 208000007048 Polymyalgia Rheumatica Diseases 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 206010062519 Poor quality sleep Diseases 0.000 description 1
- 241001135549 Porcine epidemic diarrhea virus Species 0.000 description 1
- 241000156302 Porcine hemagglutinating encephalomyelitis virus Species 0.000 description 1
- 241000702619 Porcine parvovirus Species 0.000 description 1
- 208000004347 Postpericardiotomy Syndrome Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 208000037534 Progressive hemifacial atrophy Diseases 0.000 description 1
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 1
- 241000150258 Prospect Hill orthohantavirus Species 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 241000621172 Pseudocowpox virus Species 0.000 description 1
- 208000001431 Psychomotor Agitation Diseases 0.000 description 1
- 208000003670 Pure Red-Cell Aplasia Diseases 0.000 description 1
- 241000569181 Quailpox virus Species 0.000 description 1
- 206010037742 Rabies Diseases 0.000 description 1
- 241000702434 Raccoon parvovirus Species 0.000 description 1
- 241000700638 Raccoonpox virus Species 0.000 description 1
- 208000012322 Raynaud phenomenon Diseases 0.000 description 1
- 230000010799 Receptor Interactions Effects 0.000 description 1
- 201000001947 Reflex Sympathetic Dystrophy Diseases 0.000 description 1
- 208000033464 Reiter syndrome Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 241000725643 Respiratory syncytial virus Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 208000005793 Restless legs syndrome Diseases 0.000 description 1
- 206010038743 Restlessness Diseases 0.000 description 1
- 206010038979 Retroperitoneal fibrosis Diseases 0.000 description 1
- 241000701037 Rhadinovirus Species 0.000 description 1
- 241000701794 Rhizidiovirus Species 0.000 description 1
- 241000713124 Rift Valley fever virus Species 0.000 description 1
- 241000711897 Rinderpest morbillivirus Species 0.000 description 1
- 241000710942 Ross River virus Species 0.000 description 1
- 241000702670 Rotavirus Species 0.000 description 1
- 241000714474 Rous sarcoma virus Species 0.000 description 1
- 241000710799 Rubella virus Species 0.000 description 1
- 241000710801 Rubivirus Species 0.000 description 1
- 241000315672 SARS coronavirus Species 0.000 description 1
- 241000608282 Sagiyama virus Species 0.000 description 1
- 241000701026 Saimiriine alphaherpesvirus 1 Species 0.000 description 1
- 241000701062 Saimiriine gammaherpesvirus 2 Species 0.000 description 1
- 241001135555 Sandfly fever Sicilian virus Species 0.000 description 1
- 241000479163 Sandjimba virus Species 0.000 description 1
- 241000593989 Scardinius erythrophthalmus Species 0.000 description 1
- 206010039705 Scleritis Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 241001123657 Seal parapoxvirus Species 0.000 description 1
- 208000005560 Self Mutilation Diseases 0.000 description 1
- 241000710961 Semliki Forest virus Species 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 241000700665 Sheeppox virus Species 0.000 description 1
- 229910007161 Si(CH3)3 Inorganic materials 0.000 description 1
- 208000003252 Signet Ring Cell Carcinoma Diseases 0.000 description 1
- 241000713656 Simian foamy virus Species 0.000 description 1
- 241000710192 Simian hepatitis A virus Species 0.000 description 1
- 241000713311 Simian immunodeficiency virus Species 0.000 description 1
- 241000580858 Simian-Human immunodeficiency virus Species 0.000 description 1
- 241000150288 Sin Nombre orthohantavirus Species 0.000 description 1
- 241000710960 Sindbis virus Species 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 244000258044 Solanum gilo Species 0.000 description 1
- 235000018650 Solanum gilo Nutrition 0.000 description 1
- 240000003768 Solanum lycopersicum Species 0.000 description 1
- 241000256248 Spodoptera Species 0.000 description 1
- 241000713675 Spumavirus Species 0.000 description 1
- 241000269319 Squalius cephalus Species 0.000 description 1
- 241001476589 Squirrel fibroma virus Species 0.000 description 1
- 241000713820 Squirrel monkey retrovirus Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 206010072148 Stiff-Person syndrome Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 241000702287 Sugarcane streak virus Species 0.000 description 1
- 241001485053 Suid betaherpesvirus 2 Species 0.000 description 1
- 241000700568 Suipoxvirus Species 0.000 description 1
- 206010042553 Superficial spreading melanoma stage unspecified Diseases 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 208000002286 Susac Syndrome Diseases 0.000 description 1
- 241000700565 Swinepox virus Species 0.000 description 1
- 206010042742 Sympathetic ophthalmia Diseases 0.000 description 1
- 201000011176 T-cell adult acute lymphocytic leukemia Diseases 0.000 description 1
- 206010042987 T-cell type acute leukaemia Diseases 0.000 description 1
- 241000712908 Tacaribe mammarenavirus Species 0.000 description 1
- 208000001106 Takayasu Arteritis Diseases 0.000 description 1
- 241000404000 Tanapox virus Species 0.000 description 1
- 241001137863 Taterapox virus Species 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010071574 Testicular autoimmunity Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 241000710209 Theiler's encephalomyelitis virus Species 0.000 description 1
- 240000001068 Thogoto virus Species 0.000 description 1
- 241000150291 Thottapalayam orthohantavirus Species 0.000 description 1
- 206010043561 Thrombocytopenic purpura Diseases 0.000 description 1
- 241000710771 Tick-borne encephalitis virus Species 0.000 description 1
- 241001125862 Tinca tinca Species 0.000 description 1
- 241000341969 Tioman virus Species 0.000 description 1
- 206010051526 Tolosa-Hunt syndrome Diseases 0.000 description 1
- 241000711517 Torovirus Species 0.000 description 1
- 241000711484 Transmissible gastroenteritis virus Species 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- 241000223109 Trypanosoma cruzi Species 0.000 description 1
- 208000004062 Tumor Virus Infections Diseases 0.000 description 1
- 241001329715 Tupaia virus Species 0.000 description 1
- 241000711955 Turkey rhinotracheitis virus Species 0.000 description 1
- 241000385708 Turkeypox virus Species 0.000 description 1
- 208000026928 Turner syndrome Diseases 0.000 description 1
- 108700036309 Type I Plasminogen Deficiency Proteins 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 206010064996 Ulcerative keratitis Diseases 0.000 description 1
- 241000608278 Una virus Species 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 241000713152 Uukuniemi virus Species 0.000 description 1
- 206010046980 Varicella Diseases 0.000 description 1
- 241000701067 Varicellovirus Species 0.000 description 1
- 241000726423 Variola major virus Species 0.000 description 1
- 201000009693 Venezuelan hemorrhagic fever Diseases 0.000 description 1
- 241000711970 Vesiculovirus Species 0.000 description 1
- 241000725110 Vilyuisk human encephalomyelitis virus Species 0.000 description 1
- 241000271897 Viperidae Species 0.000 description 1
- 241000711825 Viral hemorrhagic septicemia virus Species 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 208000010094 Visna Diseases 0.000 description 1
- 241000713325 Visna/maedi virus Species 0.000 description 1
- 241001137865 Volepox virus Species 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- 241000120535 Wallal virus Species 0.000 description 1
- 241000120524 Warrego virus Species 0.000 description 1
- 208000000260 Warts Diseases 0.000 description 1
- 241000710886 West Nile virus Species 0.000 description 1
- 241000231320 Whataroa virus Species 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 241001492404 Woodchuck hepatitis virus Species 0.000 description 1
- 241000714205 Woolly monkey sarcoma virus Species 0.000 description 1
- 241000702661 Wound tumor virus Species 0.000 description 1
- 241000700574 Yatapoxvirus Species 0.000 description 1
- 241000710772 Yellow fever virus Species 0.000 description 1
- 208000012018 Yolk sac tumor Diseases 0.000 description 1
- 241001481505 Yug Bogdanovac vesiculovirus Species 0.000 description 1
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 208000006336 acinar cell carcinoma Diseases 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 206010000583 acral lentiginous melanoma Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 208000020700 acute megakaryocytic leukemia Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 210000002534 adenoid Anatomy 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 201000006966 adult T-cell leukemia Diseases 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000036626 alertness Effects 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 235000020224 almond Nutrition 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 208000008524 alveolar soft part sarcoma Diseases 0.000 description 1
- 208000006431 amelanotic melanoma Diseases 0.000 description 1
- 230000002707 ameloblastic effect Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 206010002022 amyloidosis Diseases 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000003510 anti-fibrotic effect Effects 0.000 description 1
- 230000003579 anti-obesity Effects 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 206010003230 arteritis Diseases 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 244000309743 astrovirus Species 0.000 description 1
- 229940090047 auto-injector Drugs 0.000 description 1
- 208000006424 autoimmune oophoritis Diseases 0.000 description 1
- 201000009780 autoimmune polyendocrine syndrome type 2 Diseases 0.000 description 1
- 206010071578 autoimmune retinopathy Diseases 0.000 description 1
- 208000010928 autoimmune thyroid disease Diseases 0.000 description 1
- 208000029407 autoimmune urticaria Diseases 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000003376 axonal effect Effects 0.000 description 1
- 206010003882 axonal neuropathy Diseases 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 208000016894 basaloid carcinoma Diseases 0.000 description 1
- 201000000450 basaloid squamous cell carcinoma Diseases 0.000 description 1
- 208000003373 basosquamous carcinoma Diseases 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000003969 blast cell Anatomy 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 208000008921 border disease Diseases 0.000 description 1
- 201000009480 botryoid rhabdomyosarcoma Diseases 0.000 description 1
- 201000010983 breast ductal carcinoma Diseases 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 229940065144 cannabinoids Drugs 0.000 description 1
- 239000001722 capsicum frutescens oleoresin Substances 0.000 description 1
- 239000001390 capsicum minimum Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 208000002458 carcinoid tumor Diseases 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000013626 chemical specie Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 208000021668 chronic eosinophilic leukemia Diseases 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000013507 chronic prostatitis Diseases 0.000 description 1
- 208000024376 chronic urticaria Diseases 0.000 description 1
- 201000010002 cicatricial pemphigoid Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000005354 coacervation Methods 0.000 description 1
- 239000000701 coagulant Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 230000004633 cognitive health Effects 0.000 description 1
- 230000001113 coital effect Effects 0.000 description 1
- 238000001246 colloidal dispersion Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 201000011050 comedo carcinoma Diseases 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 201000004395 congenital heart block Diseases 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000012733 controlled-release (CR) dosage form Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 201000011063 cribriform carcinoma Diseases 0.000 description 1
- 201000003278 cryoglobulinemia Diseases 0.000 description 1
- 238000000315 cryotherapy Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000003210 demyelinating effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- KAUVQQXNCKESLC-UHFFFAOYSA-N docosahexaenoic acid (DHA) Natural products COC(=O)C(C)NOCC1=CC=CC=C1 KAUVQQXNCKESLC-UHFFFAOYSA-N 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 208000019479 dysautonomia Diseases 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 208000001991 endodermal sinus tumor Diseases 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 201000000708 eosinophilic esophagitis Diseases 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 208000009724 equine infectious anemia Diseases 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 210000003020 exocrine pancreas Anatomy 0.000 description 1
- 208000002980 facial hemiatrophy Diseases 0.000 description 1
- 235000020937 fasting conditions Nutrition 0.000 description 1
- 229940125741 fatty acid modulator Drugs 0.000 description 1
- 230000004634 feeding behavior Effects 0.000 description 1
- 230000003328 fibroblastic effect Effects 0.000 description 1
- 206010016629 fibroma Diseases 0.000 description 1
- 235000019688 fish Nutrition 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 208000018090 giant cell myocarditis Diseases 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075529 glyceryl stearate Drugs 0.000 description 1
- 208000017750 granulocytic sarcoma Diseases 0.000 description 1
- 210000002503 granulosa cell Anatomy 0.000 description 1
- 230000003370 grooming effect Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 230000037219 healthy weight Effects 0.000 description 1
- 230000001894 hemadsorption Effects 0.000 description 1
- 208000007475 hemolytic anemia Diseases 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 210000004024 hepatic stellate cell Anatomy 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 1
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 210000004276 hyalin Anatomy 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 201000006362 hypersensitivity vasculitis Diseases 0.000 description 1
- 230000036031 hyperthermia Effects 0.000 description 1
- 206010021198 ichthyosis Diseases 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 208000015446 immunoglobulin a vasculitis Diseases 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 201000008319 inclusion body myositis Diseases 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000037951 infantile gastroenteritis Diseases 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000006362 insulin response pathway Effects 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000001865 kupffer cell Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 1
- 208000003849 large cell carcinoma Diseases 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 208000011080 lentigo maligna melanoma Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000000610 leukopenic effect Effects 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 206010071570 ligneous conjunctivitis Diseases 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 201000000014 lung giant cell carcinoma Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 201000000966 lung oat cell carcinoma Diseases 0.000 description 1
- 208000018555 lymphatic system disease Diseases 0.000 description 1
- 201000011649 lymphoblastic lymphoma Diseases 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 201000000564 macroglobulinemia Diseases 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 206010061526 malignant mesenchymoma Diseases 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 208000000516 mast-cell leukemia Diseases 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000005541 medical transmission Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 230000000684 melanotic effect Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 206010063344 microscopic polyangiitis Diseases 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 description 1
- 208000001611 myxosarcoma Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002088 nanocapsule Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 201000003631 narcolepsy Diseases 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 230000002276 neurotropic effect Effects 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 210000002445 nipple Anatomy 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 201000000032 nodular malignant melanoma Diseases 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 208000029809 non-keratinizing sinonasal squamous cell carcinoma Diseases 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 208000015200 ocular cicatricial pemphigoid Diseases 0.000 description 1
- 239000008601 oleoresin Substances 0.000 description 1
- BOWVQLFMWHZBEF-KTKRTIGZSA-N oleoyl ethanolamide Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)NCCO BOWVQLFMWHZBEF-KTKRTIGZSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 201000005580 palindromic rheumatism Diseases 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 235000021400 peanut butter Nutrition 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 208000019899 phobic disease Diseases 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical class OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000037074 physically active Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 201000006292 polyarteritis nodosa Diseases 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000010491 poppyseed oil Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 208000018290 primary dysautonomia Diseases 0.000 description 1
- 201000000742 primary sclerosing cholangitis Diseases 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 208000029817 pulmonary adenocarcinoma in situ Diseases 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 208000010540 rapid respiration Diseases 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 231100000272 reduced body weight Toxicity 0.000 description 1
- 208000009169 relapsing polychondritis Diseases 0.000 description 1
- 201000006845 reticulosarcoma Diseases 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 201000005404 rubella Diseases 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 201000007416 salivary gland adenoid cystic carcinoma Diseases 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 208000014212 sarcomatoid carcinoma Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 208000004259 scirrhous adenocarcinoma Diseases 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000000276 sedentary effect Effects 0.000 description 1
- 201000008123 signet ring cell adenocarcinoma Diseases 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 201000010153 skin papilloma Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 235000014214 soft drink Nutrition 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 208000011584 spitz nevus Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 208000003265 stomatitis Diseases 0.000 description 1
- 208000028210 stromal sarcoma Diseases 0.000 description 1
- 201000010033 subleukemic leukemia Diseases 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 125000005717 substituted cycloalkylene group Chemical group 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 208000030457 superficial spreading melanoma Diseases 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 206010042863 synovial sarcoma Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000002381 testicular Effects 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000005457 triglyceride group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 208000022810 undifferentiated (embryonal) sarcoma Diseases 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 241000701451 unidentified granulovirus Species 0.000 description 1
- 241000007181 unidentified human coronavirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 230000002477 vacuolizing effect Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 208000008662 verrucous carcinoma Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- 229940051021 yellow-fever virus Drugs 0.000 description 1
- YKPUWZUDDOIDPM-VURMDHGXSA-N zucapsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C/C(C)C)=CC=C1O YKPUWZUDDOIDPM-VURMDHGXSA-N 0.000 description 1
- 229960002860 zucapsaicin Drugs 0.000 description 1
- DTOSIQBPPRVQHS-UHFFFAOYSA-N α-Linolenic acid Chemical compound CCC=CCC=CCC=CCCCCCCCC(O)=O DTOSIQBPPRVQHS-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Diabetes (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Child & Adolescent Psychology (AREA)
- Gastroenterology & Hepatology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Provided herein are combinations of capsaicin and TrpV1 modulators that are useful for treating capsaicin-responsive diseases or disorders.
Description
2 METHODS OF USE THEREOF
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/126,467 filed on December 16, 2020, which is incorporated by reference in its entirety.
BACKGROUND
[0002] A need exists in the medicinal arts for the effective treatment of capsaicin-responsive diseases and disorders. Such diseases and disorders include, but are not limited to, a cell proliferative disease (e.g., a cancer), obesity, diabetes, a bacterial infection, a cardiovascular disease, a neurodegenerative disease or disorder, an inflammatory disease or disorder, a comorbidity, autoimmune disease, hypercholesterolemia, and/or mood disorders.
BRIEF SUMMARY
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/126,467 filed on December 16, 2020, which is incorporated by reference in its entirety.
BACKGROUND
[0002] A need exists in the medicinal arts for the effective treatment of capsaicin-responsive diseases and disorders. Such diseases and disorders include, but are not limited to, a cell proliferative disease (e.g., a cancer), obesity, diabetes, a bacterial infection, a cardiovascular disease, a neurodegenerative disease or disorder, an inflammatory disease or disorder, a comorbidity, autoimmune disease, hypercholesterolemia, and/or mood disorders.
BRIEF SUMMARY
[0003] An aspect described herein is a composition, comprising:
(i) a compound of structural Formula (I):
n1 0_ n3 or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨0R1A, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted Ci-o alkyl; and R1A is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and (ii) a fatty acid, wherein a ratio of the compound of Formula (1) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and the fatty acid is in a range of about 1:5 to about 1:1000.
In one feature, the compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 0.1%(w/v) to about 50% (w/v). In one feature, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 10%
(w/v). In one feature, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of less than about 2% (w/v). In one feature, the fatty acid is a cannabinoid. In one feature, the fatty acid is a polyunsaturated fatty acid (PUFA). In one feature, the PUFA is anandamide. In one feature, the PUFA is a cannabinoid. In one feature, the PUFA is a n-3 PUFA. In one feature, the PUFA is a n-6 PUFA. In one feature, the fatty acid is an omega-3 fatty acid. In one feature, the omega-3 fatty acid is DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid), LNA (linolenic acid), or combinations thereof. In one feature, the omega-3 fatty acid is DHA (docosahexaenoic acid), EPA
(eicosapentaenoic acid), LNA (linolenic acid), or combinations thereof In one feature, the fatty acid is oleic acid or erucic acid. In one feature, a ratio of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and the fatty acid is in a range of about 1:20 to about 1:100. In one feature, a ratio of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and the fatty acid is about 1:60. In one feature, the composition is in a form for oral dosing or administration. In one feature, the compound of structural Formula (I) has structural Formula (I-A):
Y R1.1 C
X
n1 0 n3 (I-A), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
R1=1 is hydrogen, halogen, ¨MOJA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R'2 is hydrogen, halogen, ¨OR' 2A, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and R1.1A and R1.2A are independently hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
In one feature, R" is CH3; and R1.2 is OH. In one feature, X is 0. In one feature, X is NH. In one a a feature, = is a double bond. In one feature, = is a single bond. In one feature, n1 is 2. In one feature, n1 is 1. In one feature, n1 is 0. In one feature. R2 is unsubstituted alkyl. In one feature, R2 is ¨CH(CH3)2 or ¨CH3. In one feature, the compound is at least one of:
HO HO Si HO HO
HO HO
HO HO
HO oil HO is , or HO
0 =
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
HO
In one feature, the compound is: 0 or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof. In one feature, the compound of structural Formula (I) is capsaicin.
In one feature, the compound of structural Formula (I) is dihydrocapsaicin.
(i) a compound of structural Formula (I):
n1 0_ n3 or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨0R1A, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted Ci-o alkyl; and R1A is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and (ii) a fatty acid, wherein a ratio of the compound of Formula (1) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and the fatty acid is in a range of about 1:5 to about 1:1000.
In one feature, the compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 0.1%(w/v) to about 50% (w/v). In one feature, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 10%
(w/v). In one feature, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of less than about 2% (w/v). In one feature, the fatty acid is a cannabinoid. In one feature, the fatty acid is a polyunsaturated fatty acid (PUFA). In one feature, the PUFA is anandamide. In one feature, the PUFA is a cannabinoid. In one feature, the PUFA is a n-3 PUFA. In one feature, the PUFA is a n-6 PUFA. In one feature, the fatty acid is an omega-3 fatty acid. In one feature, the omega-3 fatty acid is DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid), LNA (linolenic acid), or combinations thereof. In one feature, the omega-3 fatty acid is DHA (docosahexaenoic acid), EPA
(eicosapentaenoic acid), LNA (linolenic acid), or combinations thereof In one feature, the fatty acid is oleic acid or erucic acid. In one feature, a ratio of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and the fatty acid is in a range of about 1:20 to about 1:100. In one feature, a ratio of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and the fatty acid is about 1:60. In one feature, the composition is in a form for oral dosing or administration. In one feature, the compound of structural Formula (I) has structural Formula (I-A):
Y R1.1 C
X
n1 0 n3 (I-A), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
R1=1 is hydrogen, halogen, ¨MOJA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R'2 is hydrogen, halogen, ¨OR' 2A, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and R1.1A and R1.2A are independently hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
In one feature, R" is CH3; and R1.2 is OH. In one feature, X is 0. In one feature, X is NH. In one a a feature, = is a double bond. In one feature, = is a single bond. In one feature, n1 is 2. In one feature, n1 is 1. In one feature, n1 is 0. In one feature. R2 is unsubstituted alkyl. In one feature, R2 is ¨CH(CH3)2 or ¨CH3. In one feature, the compound is at least one of:
HO HO Si HO HO
HO HO
HO HO
HO oil HO is , or HO
0 =
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
HO
In one feature, the compound is: 0 or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof. In one feature, the compound of structural Formula (I) is capsaicin.
In one feature, the compound of structural Formula (I) is dihydrocapsaicin.
[0004] An aspect described herein is a method of treating or preventing a capsaicin-responsive disease or disorder, comprising administering to a subject in need thereof the composition described herein. In one feature, the disease or disorder is a cell proliferative disease, obesity, diabetes, a bacterial infection, a cardiovascular disease, a neurodegenerative disease or disorder, an inflammatory disease or disorder, a comorbidity, an autoimmune disease, hypercholesterolemia or a mood disorder. In one feature, the mood disorder is depression. In one feature, the inflammatory disease or disorder is rheumatoid arthritis. In one feature, the cell proliferative disease is a cancer. In one feature, the disorder is diabetes or obesity. In one feature, the comorbidity is chronic kidney disease, stroke, congestive heart failure, dementia, schizophrenia, hepatitis, autism spectrum disorder, HIV, or a combination thereof. In one feature, the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite. pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally. In one feature, the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally via a suspension or solution. In one feature, the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally via a solid dosage form. In one feature, form is a tablet or capsule. In one feature, the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by inhalation, nebulization, or nasal delivery. In one feature, the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by inhalation via a vaporizer. In one feature, the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered parenterally. In one feature, the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered via parenteral injection, infusion, or implantation. In one feature, the parenteral injection is intravenous, intramuscular, subcutaneous, or intradermal. In one feature, the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered via a suppository. In one feature, the compound of structural Formula (1) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered cutaneous or transdermal delivery. In one feature, the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by sublingual or buccal delivery. In one feature, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the fatty acid are administered simultaneously, approximately simultaneously, or sequentially, in any order. In one feature, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the fatty acid are administered simultaneously or approximately simultaneously. In one feature, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the fatty acid are administered sequentially. In one feature, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is released before the fatty acid. In one feature, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is released after the fatty acid.
BRIEF DESCRIPTION OF THE DRAWINGS
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] The novel features of the invention are set forth with particularity in the appended claims. A
better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
[0006] Fig. 1 is a graph depicting the cumulative food intake, days 0-14. Data expressed as mean+SEM, n=12.
[0007] Fig. 2 is a graph depicting the effects of capsaicinoid-EPA
combinations on hepatic steatosis (% lipid fractional area in H&E staining). Data are expressed as mean+SEM, n=12.
combinations on hepatic steatosis (% lipid fractional area in H&E staining). Data are expressed as mean+SEM, n=12.
[0008] Fig. 3 is a graph depicting the effects of capsaicinoid-EPA
combinations on hepatic stellate cell activation (a-SMA 5 fractional area via 1HC). Data are expressed as mean+SEM, n=12.
combinations on hepatic stellate cell activation (a-SMA 5 fractional area via 1HC). Data are expressed as mean+SEM, n=12.
[0009] Fig. 4 is a graph depicting the effects of capsaicinoid-EPA
combinations on fibrosis (Collal % fractional area via IHC). Data are expressed as mean+SEM, n=12.
combinations on fibrosis (Collal % fractional area via IHC). Data are expressed as mean+SEM, n=12.
[0010] Fig. 5 is a graph depicting the effects of capsaicinoid-OA combinations on body weight (expressed as % of day 0 weight). Data are expressed as mean+SEM, n=12.
[0011] Fig. 6 is a graph depicting the effects of capsaicinoid-OA combinations on body fat loss (left panel) and body fat expressed as % of body weight (right panel). Data are expressed as mean+SEM, n=12.
[0012] Figs. 7A-7D depict the calcium tracings of DRG neurons. Fig. 7A depicts the capsaicin control and Fig. 7B depicts the DHC control. Fig. 7C depicts capsaicin+0A.
Fig. 7D depicts DHC+0A.
INCORPORATION BY REFERENCE
100131 All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
DETAILED DESCRIPTION
[0014] Provided herein are, for example, compositions for treating and/or preventing a capsaicin-responsive disease or disorder. Also provided herein are, for example, methods of treating and/or preventing a capsaicin-responsive disease or disorder.
Definitions 100151 The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.
[0016] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals, having the number of carbon atoms designated (i.e., CI-Cto means one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-0-).
[0017] The term "heteroalkyl,- by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., 0, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
The heteroatom(s) (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -0-13-CH7-0-CH3, -C1-13-0-13-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(0)-CH3, -CH3-CH2-S(0)2-CH3, -CH=CH-O-CH3, -5i(CH3)3, -CH3-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -0-CH3, -0-CH3-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-0-Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., 0, N, S, Si, or P). A
heteroalkyl moiety may include two optionally different heteroatoms (e.g., 0, N, S. Si, or P). A
heteroalkyl moiety may include three optionally different heteroatoms (e.g., 0, N, S, Si, or P). A
heteroalkyl moiety may include four optionally different heteroatoms (e.g., 0, N, S, Si, or P). A
heteroalkyl moiety may include five optionally different heteroatoms (e.g., 0, N, S, Si, or P). A
heteroalkyl moiety may include up to eight optionally different heteroatoms (e.g., 0, N, S, Si, or P).
[0018] Each of the above terms (e.g., "alkyl," "heteroalkyl," etc.) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
[0019] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =0, =NR', =N-OR', -NR'R", -SR', -halogen, -SiR'R"R", -0C(0)R', -C(0)R', -CO2R', -CONR'R", -0C(0)NR'R", -NR"C(0)R, -NR-C(0)NR"R", -NR"C(0)2R', -NR-C(NR'R"R"')=NR'"', -NR-C(NR'R")=NR'", -S(0)R', -S(0)2R', -S(0)2NR'R", -NRS 02R', -NR`NR"R", -0NR'R", -NR'C(0)NR"NR"R'"', -CN, -NO2, -NR'SO2R", -NR'C(0)R", -NR'C(0)-OR", -NR'OR", in a number ranging from zero to (2m'+1), where m is the total number of carbon atoms in such radical. R, R', R", R", and R" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
When a compound described herein includes more than one R group, for example, each of the R
groups is independently selected as are each R', R", R", and R" group when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(0)CH3, -C(0)CF3, -C(0)CH2OCH3, and the like).
[0020] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R", -SR', -halogen, -SiR'R"R", -0C(0)R', -C(0)R', -CO2R', -CONR'R", -0C(0)NR'R", -NR"C(0)R', -NR'47(0)NR"R", -NR"C(0)2R', -NR-C(NR'R"R'")=NR", -NR-C(NR'R")=NR"', -S(0)R', -S(0)2R', -S(0)2NR'R", -NRS 02R', -NR`NR"R'", -0NR'R", -NR'C(0)NR"NR'"R", -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(Ci-C4)alkoxy, and fluoro(CI-C4)alkyl, -NR'SO2R", -NR'C(0)R", -NR'C(0)-OR", -NR'OR", in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R", R", and R" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R", and R" groups when more than one of these groups is present.
[0021] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.
[0022] A "substituent group," as used herein, means a group selected from the following moieties:
(A) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -SO4H, -S02NH2, -NHNH2, -0N142, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, -NHC= (0)H, -NHC(0)-0H, -NHOH, -0CF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:
(i) oxo, halogen, -CF3, -CN, -OH, -NI-I2, -COOH, -CONH2, -NO2, -SH, -S03H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, -NHC= (0)H, -NHC(0)-0H, -NHOH, -0CF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:
(a) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, -NHC=
(0)H, -NHC(0)-0H, -NHOH, -0CF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalk-yl, unsubstituted heterocycl alkyl, unsubstituted aryl, unsubstituted heteroaryl, and (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, -NHC= (0)H, -NHC(0)-0H, -NHOH, -0CF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.
[0023] A "size-limited substituent" or "size-limited substituent group," as used herein, means a group selected from all of the substituents described above for a -substituent group," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted CI-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-Clo aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.
[0024] A "lower substituent" or "lower substituent group," as used herein, means a group selected from all of the substituents described above for a "substituent group,"
wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted CI-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted (26-Cm aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.
100251 In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted het eroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.
[0026] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted Ci-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3 -C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-Clo aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-Clo arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.
[0027] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycl alkyl, each substituted or unsubstituted heterocycloalk-y1 is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-Clo aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.
[0028] Certain compounds disclosed herein possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and/or isolate. The presently disclosed compounds include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E
and Z geometric isomers.
[0029] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center.
Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope hereof.
[0030] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope hereof.
[0031] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes (i.e., isotopic variants) at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (1251,, ) or carbon-14 (NC). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
[0032] It should be noted that throughout the application that alternatives are wTitten in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.
[0033] As used herein, the term "isomers" refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
[0034] The term -tautomer," as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
[0035] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.
[0036] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or "C-enriched carbon are within the scope of this disclosure.
[0037] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (1251), or carbon-14 ("C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
[0038] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.
[0039] The terms "a" or "an," as used in herein means one or more. In addition, the phrase "substituted with a[n]," as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is "substituted with an unsubstituted CI-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl," the group may contain one or more unsubstituted CI-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
[0040] The term -pharmaceutically acceptable salts- is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et at., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
[0041] Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts.
Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.
[0042] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. In embodiments, compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compounds differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but, unless specifically indicated, the salts disclosed herein are equivalent to the parent form of the compound for the purposes of the present disclosure.
[0043] In addition to salt forms, the present disclosure provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure.
Prodrugs of the compounds described herein may be converted in vivo after administration.
Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.
[0044] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
[0045] "Pharmaceutically acceptable excipient- and "pharmaceutically acceptable carrier- refer to a substance that aids the administration of a compound to and absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.
[0046] The term "contacting- may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway. In some embodiments contacting includes allowing a compound described herein to interact with mitochondrial complex I.
[0047] As defined herein, the term -inhibition," "inhibit," "inhibiting" and the like in reference to a protein-inhibitor interaction means negatively affecting (e.g. decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In
Fig. 7D depicts DHC+0A.
INCORPORATION BY REFERENCE
100131 All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
DETAILED DESCRIPTION
[0014] Provided herein are, for example, compositions for treating and/or preventing a capsaicin-responsive disease or disorder. Also provided herein are, for example, methods of treating and/or preventing a capsaicin-responsive disease or disorder.
Definitions 100151 The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.
[0016] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals, having the number of carbon atoms designated (i.e., CI-Cto means one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-0-).
[0017] The term "heteroalkyl,- by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., 0, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
The heteroatom(s) (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -0-13-CH7-0-CH3, -C1-13-0-13-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(0)-CH3, -CH3-CH2-S(0)2-CH3, -CH=CH-O-CH3, -5i(CH3)3, -CH3-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -0-CH3, -0-CH3-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-0-Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., 0, N, S, Si, or P). A
heteroalkyl moiety may include two optionally different heteroatoms (e.g., 0, N, S. Si, or P). A
heteroalkyl moiety may include three optionally different heteroatoms (e.g., 0, N, S, Si, or P). A
heteroalkyl moiety may include four optionally different heteroatoms (e.g., 0, N, S, Si, or P). A
heteroalkyl moiety may include five optionally different heteroatoms (e.g., 0, N, S, Si, or P). A
heteroalkyl moiety may include up to eight optionally different heteroatoms (e.g., 0, N, S, Si, or P).
[0018] Each of the above terms (e.g., "alkyl," "heteroalkyl," etc.) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
[0019] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =0, =NR', =N-OR', -NR'R", -SR', -halogen, -SiR'R"R", -0C(0)R', -C(0)R', -CO2R', -CONR'R", -0C(0)NR'R", -NR"C(0)R, -NR-C(0)NR"R", -NR"C(0)2R', -NR-C(NR'R"R"')=NR'"', -NR-C(NR'R")=NR'", -S(0)R', -S(0)2R', -S(0)2NR'R", -NRS 02R', -NR`NR"R", -0NR'R", -NR'C(0)NR"NR"R'"', -CN, -NO2, -NR'SO2R", -NR'C(0)R", -NR'C(0)-OR", -NR'OR", in a number ranging from zero to (2m'+1), where m is the total number of carbon atoms in such radical. R, R', R", R", and R" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
When a compound described herein includes more than one R group, for example, each of the R
groups is independently selected as are each R', R", R", and R" group when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(0)CH3, -C(0)CF3, -C(0)CH2OCH3, and the like).
[0020] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R", -SR', -halogen, -SiR'R"R", -0C(0)R', -C(0)R', -CO2R', -CONR'R", -0C(0)NR'R", -NR"C(0)R', -NR'47(0)NR"R", -NR"C(0)2R', -NR-C(NR'R"R'")=NR", -NR-C(NR'R")=NR"', -S(0)R', -S(0)2R', -S(0)2NR'R", -NRS 02R', -NR`NR"R'", -0NR'R", -NR'C(0)NR"NR'"R", -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(Ci-C4)alkoxy, and fluoro(CI-C4)alkyl, -NR'SO2R", -NR'C(0)R", -NR'C(0)-OR", -NR'OR", in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R", R", and R" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R", and R" groups when more than one of these groups is present.
[0021] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.
[0022] A "substituent group," as used herein, means a group selected from the following moieties:
(A) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -SO4H, -S02NH2, -NHNH2, -0N142, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, -NHC= (0)H, -NHC(0)-0H, -NHOH, -0CF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:
(i) oxo, halogen, -CF3, -CN, -OH, -NI-I2, -COOH, -CONH2, -NO2, -SH, -S03H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, -NHC= (0)H, -NHC(0)-0H, -NHOH, -0CF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from:
(a) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, -NHC=
(0)H, -NHC(0)-0H, -NHOH, -0CF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalk-yl, unsubstituted heterocycl alkyl, unsubstituted aryl, unsubstituted heteroaryl, and (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from: oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(0)NHNH2, -NHC=(0) NH2, -NHSO2H, -NHC= (0)H, -NHC(0)-0H, -NHOH, -0CF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.
[0023] A "size-limited substituent" or "size-limited substituent group," as used herein, means a group selected from all of the substituents described above for a -substituent group," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted CI-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-Clo aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.
[0024] A "lower substituent" or "lower substituent group," as used herein, means a group selected from all of the substituents described above for a "substituent group,"
wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted CI-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted (26-Cm aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.
100251 In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted het eroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.
[0026] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted Ci-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3 -C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-Clo aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-Clo arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.
[0027] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycl alkyl, each substituted or unsubstituted heterocycloalk-y1 is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-Clo aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.
[0028] Certain compounds disclosed herein possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and/or isolate. The presently disclosed compounds include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E
and Z geometric isomers.
[0029] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center.
Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope hereof.
[0030] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope hereof.
[0031] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes (i.e., isotopic variants) at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (1251,, ) or carbon-14 (NC). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
[0032] It should be noted that throughout the application that alternatives are wTitten in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.
[0033] As used herein, the term "isomers" refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
[0034] The term -tautomer," as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
[0035] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.
[0036] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or "C-enriched carbon are within the scope of this disclosure.
[0037] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (1251), or carbon-14 ("C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
[0038] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.
[0039] The terms "a" or "an," as used in herein means one or more. In addition, the phrase "substituted with a[n]," as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is "substituted with an unsubstituted CI-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl," the group may contain one or more unsubstituted CI-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
[0040] The term -pharmaceutically acceptable salts- is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et at., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
[0041] Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts.
Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.
[0042] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. In embodiments, compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compounds differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but, unless specifically indicated, the salts disclosed herein are equivalent to the parent form of the compound for the purposes of the present disclosure.
[0043] In addition to salt forms, the present disclosure provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure.
Prodrugs of the compounds described herein may be converted in vivo after administration.
Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.
[0044] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
[0045] "Pharmaceutically acceptable excipient- and "pharmaceutically acceptable carrier- refer to a substance that aids the administration of a compound to and absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.
[0046] The term "contacting- may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. In some embodiments contacting includes allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway. In some embodiments contacting includes allowing a compound described herein to interact with mitochondrial complex I.
[0047] As defined herein, the term -inhibition," "inhibit," "inhibiting" and the like in reference to a protein-inhibitor interaction means negatively affecting (e.g. decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In
-13 -embodiments inhibition means negatively affecting (e.g. decreasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor. In embodiments inhibition refers to reduction of a disease or symptoms of disease. In embodiments, inhibition refers to a reduction in the activity of a particular protein target. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. In embodiments, inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g. an inhibitor binds to the target protein). In embodiments, inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation).
[0048] The terms "inhibitor,- "repressor- or "antagonist- or "downregulator-interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein.
The antagonist can decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist. An antagonist prevents, reduces, inhibits, or neutralizes the activity of an agonist, and an antagonist can also prevent, inhibit, or reduce constitutive activity of a target, e.g., a target receptor, even where there is no identified agonist.
In embodiments, inhibitors are molecules that decrease, block, prevent, delay activation, inactivate, desensitize, or down-regulate, e.g., a gene, protein, ligand, receptor, or cell. An inhibitor may also be defined as a molecule that reduces, blocks, or inactivates a constitutive activity. An -antagonist" is a molecule that opposes the action(s) of an agonist.
[0049] The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders. capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
[0050] The terms "disease- or "condition- refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. The disease may be an autoimmune disease. The disease may be an inflammatory disease.
[0051] The disease may be an infectious disease. The infectious disease may be caused by a bacteria, viruses, parasites, or fungi. In some embodiments, the infectious disease is caused by Abelson leukemia virus, Abelson murine leukemia virus, Abelson's virus, Acute laryngotracheobronchitis virus, Adelaide River virus, Adeno associated virus group, Adenovirus, African horse sickness virus, African swine fever virus, AIDS virus, Aleutian mink disease parvovirus, Alpharetrovirus,
[0048] The terms "inhibitor,- "repressor- or "antagonist- or "downregulator-interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein.
The antagonist can decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist. An antagonist prevents, reduces, inhibits, or neutralizes the activity of an agonist, and an antagonist can also prevent, inhibit, or reduce constitutive activity of a target, e.g., a target receptor, even where there is no identified agonist.
In embodiments, inhibitors are molecules that decrease, block, prevent, delay activation, inactivate, desensitize, or down-regulate, e.g., a gene, protein, ligand, receptor, or cell. An inhibitor may also be defined as a molecule that reduces, blocks, or inactivates a constitutive activity. An -antagonist" is a molecule that opposes the action(s) of an agonist.
[0049] The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders. capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
[0050] The terms "disease- or "condition- refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. The disease may be an autoimmune disease. The disease may be an inflammatory disease.
[0051] The disease may be an infectious disease. The infectious disease may be caused by a bacteria, viruses, parasites, or fungi. In some embodiments, the infectious disease is caused by Abelson leukemia virus, Abelson murine leukemia virus, Abelson's virus, Acute laryngotracheobronchitis virus, Adelaide River virus, Adeno associated virus group, Adenovirus, African horse sickness virus, African swine fever virus, AIDS virus, Aleutian mink disease parvovirus, Alpharetrovirus,
-14-Alphavirus, ALV related virus, Amapari virus, Aphthovirus, Aquareovirus, Arbovirus, Arbovirus C, arbovirus group A, arbovirus group B, Arenavirus group, Argentine hemorrhagic fever virus, Argentine hemorrhagic fever virus, Arterivirus, Astrovirus, Ateline herpesvirus group, Aujezky's disease virus, Aura virus, Ausduk disease virus, Australian bat lyssavirus, Aviadenovirus, avian erythroblastosis virus, avian infectious bronchitis virus, avian leukemia virus, avian leukosis virus, avian lymphomatosis virus, avian myeloblastosis virus, avian paramyxovirus, avian pneumoencephalitis virus, avian reticuloendotheliosis virus, avian sarcoma virus, avian type C
retrovirus group, Avihepadnavirus, Avipoxvirus, B virus, B19 virus, Babanki virus, baboon herpesvirus, baculovirus, Barmah Forest virus, Bebaru virus, Berrimah virus, Betaretrovirus, Birnavirus, Bittner virus, BK virus, Black Creek Canal virus, bluetongue virus, Bolivian hemorrhagic fever virus, Boma disease virus, border disease of sheep virus, borna virus, bovine alphaherpesvirus 1, bovine alphaherpesvirus 2, bovine coronavirus, bovine ephemeral fever virus, bovine immunodeficiency virus, bovine leukemia virus, bovine leukosis virus, bovine mammillitis virus, bovine papillomavirus, bovine papular stomatitis virus, bovine parvovirus, bovine syncytial virus, bovine type C oncovirus, bovine viral diarrhea virus, Buggy Creek virus, bullet shaped virus group, Bunyamwera virus supergroup, Bunyavirus, Burkitt's lymphoma virus, Bwamba Fever, CA virus, Calicivirus, California encephalitis virus, camelpox virus, canarypox virus, canid herpesvirus, canine coronavirus, canine distemper virus, canine herpesvirus, canine minute virus, canine parvovirus, Cano Delgadito virus, caprine arthritis virus, caprine encephalitis virus, Caprine Herpes Virus, Capripox virus, Cardiovirus, caviid herpesvirus 1, Cercopithecid herpesvirus 1, cercopithecine herpesvirus 1, Cercopithecine herpesvirus 2, Chandipura virus, Changuinola virus, channel catfish virus, Charleville virus, chickenpox virus, Chikungunya virus, chimpanzee herpesvirus, chub reovirus, chum salmon virus, Cocal virus, Coho salmon reovirus, coital exanthema virus, Colorado tick fever virus, Coltivirus, Columbia SK virus, common cold virus, contagious eethyma virus, contagious pustular dermatitis virus, Coronavirus, Corriparta virus, coryza virus, cowpox virus, coxsackie virus, CPV (cytoplasmic polyhedrosis virus), cricket paralysis virus, Crimean-Congo hemorrhagic fever virus, croup associated virus, Cryptovirus, Cypovirus, Cytomegalovirus, cytomegalovirus group, cytoplasmic polyhedrosis virus, deer papillomavirus, deltaretrovirus, dengue virus, Densovirus, Dependovirus, Dhori virus, diploma virus, Drosophila C
virus, duck hepatitis B
virus, duck hepatitis virus 1, duck hepatitis virus 2, duovirus, Duvenhage virus, Deformed wing virus DWV, eastern equine encephalitis virus, eastern equine encephalomyelitis virus, EB virus, Ebola virus, Ebola-like virus, echo virus, echovirus, echovirus 10, echovirus 28, echovirus 9, ectromelia virus, EEE virus, ETA virus, ETA virus, encephalitis virus, encephalomyocarditis group virus, encephalomyocarditis virus, Enterovirus, enzyme elevating virus, enzyme elevating virus (LDH), epidemic hemorrhagic fever virus, epizootic hemorrhagic disease virus, Epstein-Barr virus, equid alphaherpesvirus 1, equid alphaherpesvirus 4, equid herpesvirus 2, equine abortion virus, equine
retrovirus group, Avihepadnavirus, Avipoxvirus, B virus, B19 virus, Babanki virus, baboon herpesvirus, baculovirus, Barmah Forest virus, Bebaru virus, Berrimah virus, Betaretrovirus, Birnavirus, Bittner virus, BK virus, Black Creek Canal virus, bluetongue virus, Bolivian hemorrhagic fever virus, Boma disease virus, border disease of sheep virus, borna virus, bovine alphaherpesvirus 1, bovine alphaherpesvirus 2, bovine coronavirus, bovine ephemeral fever virus, bovine immunodeficiency virus, bovine leukemia virus, bovine leukosis virus, bovine mammillitis virus, bovine papillomavirus, bovine papular stomatitis virus, bovine parvovirus, bovine syncytial virus, bovine type C oncovirus, bovine viral diarrhea virus, Buggy Creek virus, bullet shaped virus group, Bunyamwera virus supergroup, Bunyavirus, Burkitt's lymphoma virus, Bwamba Fever, CA virus, Calicivirus, California encephalitis virus, camelpox virus, canarypox virus, canid herpesvirus, canine coronavirus, canine distemper virus, canine herpesvirus, canine minute virus, canine parvovirus, Cano Delgadito virus, caprine arthritis virus, caprine encephalitis virus, Caprine Herpes Virus, Capripox virus, Cardiovirus, caviid herpesvirus 1, Cercopithecid herpesvirus 1, cercopithecine herpesvirus 1, Cercopithecine herpesvirus 2, Chandipura virus, Changuinola virus, channel catfish virus, Charleville virus, chickenpox virus, Chikungunya virus, chimpanzee herpesvirus, chub reovirus, chum salmon virus, Cocal virus, Coho salmon reovirus, coital exanthema virus, Colorado tick fever virus, Coltivirus, Columbia SK virus, common cold virus, contagious eethyma virus, contagious pustular dermatitis virus, Coronavirus, Corriparta virus, coryza virus, cowpox virus, coxsackie virus, CPV (cytoplasmic polyhedrosis virus), cricket paralysis virus, Crimean-Congo hemorrhagic fever virus, croup associated virus, Cryptovirus, Cypovirus, Cytomegalovirus, cytomegalovirus group, cytoplasmic polyhedrosis virus, deer papillomavirus, deltaretrovirus, dengue virus, Densovirus, Dependovirus, Dhori virus, diploma virus, Drosophila C
virus, duck hepatitis B
virus, duck hepatitis virus 1, duck hepatitis virus 2, duovirus, Duvenhage virus, Deformed wing virus DWV, eastern equine encephalitis virus, eastern equine encephalomyelitis virus, EB virus, Ebola virus, Ebola-like virus, echo virus, echovirus, echovirus 10, echovirus 28, echovirus 9, ectromelia virus, EEE virus, ETA virus, ETA virus, encephalitis virus, encephalomyocarditis group virus, encephalomyocarditis virus, Enterovirus, enzyme elevating virus, enzyme elevating virus (LDH), epidemic hemorrhagic fever virus, epizootic hemorrhagic disease virus, Epstein-Barr virus, equid alphaherpesvirus 1, equid alphaherpesvirus 4, equid herpesvirus 2, equine abortion virus, equine
-15 -arteritis virus, equine encephalosis virus, equine infectious anemia virus, equine morbillivirus, equine rhinopneumonitis virus, equine rhinovirus, Eubenangu virus, European elk papillomavirus, European swine fever virus, Everglades virus, Eyach virus, felid herpesvirus 1, feline calicivirus, feline fibrosarcoma virus, feline herpesvirus, feline immunodeficiency virus, feline infectious peritonitis virus, feline leukemia/sarcoma virus, feline leukemia virus, feline panleukopenia virus, feline parvovirus, feline sarcoma virus, feline syncytial virus, Filovirus, Flanders virus, Flavivirus, foot and mouth disease virus, Fort Morgan virus, Four Corners hantavirus, fowl adenovirus 1, fowlpox virus, Friend virus, Gammaretrovirus. GB hepatitis virus, GB virus, German measles virus, Getah virus, gibbon ape leukemia virus, glandular fever virus, goatpox virus, golden shinner virus, Gonometa virus, goose parvovirus, granulosis virus, Gross' virus, ground squirrel hepatitis B virus, group A
arbovirus, Guanarito virus, guinea pig cytomegalovirus, guinea pig type C
virus, Hantaan virus, Hantavirus, hard clam reovirus, hare fibroma virus, HCMV (human cytomegalovirus), hemadsorption virus 2, hemagglutinating virus of Japan, hemorrhagic fever virus, hendra virus, Henipaviruses, Hepadnavirus, hepatitis A virus, hepatitis B virus group, hepatitis C virus, hepatitis D virus, hepatitis delta virus, hepatitis E virus, hepatitis F virus, hepatitis G virus, hepatitis nonA nonB virus, hepatitis virus, hepatitis virus (nonhuman), hepatoencephalomyelitis reovirus 3, Hepatovirus, heron hepatitis B
virus, herpes B virus, herpes simplex virus, herpes simplex virus 1, herpes simplex virus 2, herpesvirus, herpesvirus 7, Herpesvirus ateles, Herpesvirus hominis, Herpesvirus infection, Herpesvirus saimiri, Herpesvirus suis, Herpesvirus varicellae, Highlands J
virus, Hirame rhabdovirus, hog cholera virus, human adenovirus 2, human alphaherpesvirus 1, human alphaherpesvirus 2, human alphaherpesvirus 3, human B lymphotropic virus, human betaherpesvirus 5, human coronavirus, human cytomegalovirus group, human foamy virus, human gammaherpesvirus 4, human gammaherpesvirus 6, human hepatitis A virus, human herpesvirus 1 group, human herpesvirus 2 group, human herpesvirus 3 group, human herpesvirus 4 group, human herpesvirus 6, human herpesvirus 8, human immunodeficiency virus, human immodeficiency virus 1, human immunodeficiency virus 2, human papillomavirus, human T cell leukemia virus, human T cell leukemia virus 1, human T cell leukemia virus 11, human T cell leukemia virus 111, human T cell lymphoma virus I, human T cell lymphoma virus II, human T cell lymphotropic virus type 1, human T cell lymphotropic virus type 2, human T lymphotropic virus I, human T
lymphotropic virus II, human T lymphotropic virus III, Ichnovirus, infantile gastroenteritis virus, infectious bovine rhinotracheitis virus, infectious haematopoietic necrosis virus, infectious pancreatic necrosis virus, influenza virus A, influenza virus B, influenza virus C, influenza virus D, influenza virus pr8, insect iridescent virus, insect virus, iridovirus, Japanese B virus, Japanese encephalitis virus, JC virus, Junin virus, Kaposi's sarcoma-associated herpesvirus, Kemerovo virus, Kilham's rat virus, Klamath virus, Kolongo virus, Korean hemorrhagic fever virus, kumba virus. Kysanur forest disease virus, Kyzylagach virus, La Crosse virus, lactic dehydrogenase elevating virus, lactic dehydrogenase virus,
arbovirus, Guanarito virus, guinea pig cytomegalovirus, guinea pig type C
virus, Hantaan virus, Hantavirus, hard clam reovirus, hare fibroma virus, HCMV (human cytomegalovirus), hemadsorption virus 2, hemagglutinating virus of Japan, hemorrhagic fever virus, hendra virus, Henipaviruses, Hepadnavirus, hepatitis A virus, hepatitis B virus group, hepatitis C virus, hepatitis D virus, hepatitis delta virus, hepatitis E virus, hepatitis F virus, hepatitis G virus, hepatitis nonA nonB virus, hepatitis virus, hepatitis virus (nonhuman), hepatoencephalomyelitis reovirus 3, Hepatovirus, heron hepatitis B
virus, herpes B virus, herpes simplex virus, herpes simplex virus 1, herpes simplex virus 2, herpesvirus, herpesvirus 7, Herpesvirus ateles, Herpesvirus hominis, Herpesvirus infection, Herpesvirus saimiri, Herpesvirus suis, Herpesvirus varicellae, Highlands J
virus, Hirame rhabdovirus, hog cholera virus, human adenovirus 2, human alphaherpesvirus 1, human alphaherpesvirus 2, human alphaherpesvirus 3, human B lymphotropic virus, human betaherpesvirus 5, human coronavirus, human cytomegalovirus group, human foamy virus, human gammaherpesvirus 4, human gammaherpesvirus 6, human hepatitis A virus, human herpesvirus 1 group, human herpesvirus 2 group, human herpesvirus 3 group, human herpesvirus 4 group, human herpesvirus 6, human herpesvirus 8, human immunodeficiency virus, human immodeficiency virus 1, human immunodeficiency virus 2, human papillomavirus, human T cell leukemia virus, human T cell leukemia virus 1, human T cell leukemia virus 11, human T cell leukemia virus 111, human T cell lymphoma virus I, human T cell lymphoma virus II, human T cell lymphotropic virus type 1, human T cell lymphotropic virus type 2, human T lymphotropic virus I, human T
lymphotropic virus II, human T lymphotropic virus III, Ichnovirus, infantile gastroenteritis virus, infectious bovine rhinotracheitis virus, infectious haematopoietic necrosis virus, infectious pancreatic necrosis virus, influenza virus A, influenza virus B, influenza virus C, influenza virus D, influenza virus pr8, insect iridescent virus, insect virus, iridovirus, Japanese B virus, Japanese encephalitis virus, JC virus, Junin virus, Kaposi's sarcoma-associated herpesvirus, Kemerovo virus, Kilham's rat virus, Klamath virus, Kolongo virus, Korean hemorrhagic fever virus, kumba virus. Kysanur forest disease virus, Kyzylagach virus, La Crosse virus, lactic dehydrogenase elevating virus, lactic dehydrogenase virus,
-16-Lagos bat virus, Langur virus, lapine parvovirus, Lassa fever virus, Lassa virus, latent rat virus, LCM
virus, Leaky virus, Lentivirus, Leporipoxvirus, leukemia virus, leukovirus, lumpy skin disease virus, lymphadenopathy associated virus. Lymphocryptovirus, lymphocytic choriomeningitis virus, lymphoproliferative virus group, Machupo virus, mad itch virus, mammalian type B oncovirus group, mammalian type B retroviruses, mammalian type C retrovirus group, mammalian type D retroviruses, mammary tumor virus, Mapuera virus, Marburg virus, Marburg-like virus, Mason Pfizer monkey virus, Mastadenovirus, Mayaro virus, ME virus, measles virus, Menangle virus, Mengo virus, Mengovirus, Middelburg virus, milkers nodule virus, mink enteritis virus, minute virus of mice, MLV related virus, MM virus, Mokola virus, Molluscipoxvirus, Molluscum contagiosum virus, monkey B virus, monkeypox virus, Mononegavirales, Morbillivirus, Mount Elgon bat virus, mouse cytomegalovirus, mouse encephalomyelitis virus, mouse hepatitis virus, mouse K
virus, mouse leukemia virus, mouse mammary tumor virus, mouse minute virus, mouse pneumonia virus, mouse poliomyelitis virus, mouse polyomavirus, mouse sarcoma virus, mousepox virus, Mozambique virus, Mucambo virus, mucosal disease virus, mumps virus, murid betaherpesvirus 1, murid cytomegalovirus 2, murine cytomegalovirus group, murine encephalomyelitis virus, murine hepatitis virus, murine leukemia virus, murine nodule inducing virus, murine polyomavirus, murine sarcoma virus, Muromegalovirus, Murray Valley encephalitis virus, myxoma virus, Myxovirus, Myxovirus multiforme, Myxovirus parotitidis, Nairobi sheep disease virus, Nairovirus, Nanirnavirus, Nariva virus, Ndumo virus, Neethling virus, Nelson Bay virus, neurotropic virus, New World Arenavirus, newborn pneumonitis virus, Newcastle disease virus, Nipah virus, noncytopathogenic virus, Norwalk virus, nuclear polyhedrosis virus (NPV), nipple neck virus, O'nyong'nyong virus, Ockelbo virus, oncogenic virus, oncogenic viruslike particle, oncornavirus, Orbivirus, Orf virus, Oropouche virus, Orthohepadnavirus, Orthomyxovirus, Orthopoxvirus, Orthoreovirus, Orungo, ovine papillomavirus, ovine catarrhal fever virus, owl monkey herpesvirus, Palyam virus, Papillomavirus, Papillomavirus sylvilagi, Papovavirus, parainfluenza virus, parainfluenza virus type 1, parainfluenza virus type 2, parainfluenza virus type 3, parainfluenza virus type 4, Paramyxovirus, Parapoxvirus, paravaccinia virus, Parvovirus, Parvovirus B19, parvovirus group, Pestivirus. Phlebovirus, phocine distemper virus, Picodnavirus, Picornavirus, pig cytomegalovirus-pigeonpox virus, Piry virus, Pixuna virus, pneumonia virus of mice, Pneumovirus, poliomyelitis virus, poliovirus, Polydnavirus, polyhedral virus, poly oma virus, Polyomavirus, Polyomavirus bovis, Polyomavirus cercopitheci, Polyomavirus hominis 2, Polyomavirus maccacae 1, Polyomavirus muris 1, Polyomavirus muris 2, Polyomavirus papionis 1, Polyomavirus papionis 2, Polyomavirus sylvilagi, Pongine herpesvirus 1, porcine epidemic diarrhea virus, porcine hemagglutinating encephalomyelitis virus, porcine parvovirus, porcine transmissible gastroenteritis virus, porcine type C virus, pox virus, poxvirus, poxvirus variolae, Prospect Hill virus, Provirus, pseudocowpox virus, pseudorabies virus, psittacinepox virus, quailpox virus, rabbit fibroma virus, rabbit kidney vaculolating virus, rabbit papillomavirus, rabies
virus, Leaky virus, Lentivirus, Leporipoxvirus, leukemia virus, leukovirus, lumpy skin disease virus, lymphadenopathy associated virus. Lymphocryptovirus, lymphocytic choriomeningitis virus, lymphoproliferative virus group, Machupo virus, mad itch virus, mammalian type B oncovirus group, mammalian type B retroviruses, mammalian type C retrovirus group, mammalian type D retroviruses, mammary tumor virus, Mapuera virus, Marburg virus, Marburg-like virus, Mason Pfizer monkey virus, Mastadenovirus, Mayaro virus, ME virus, measles virus, Menangle virus, Mengo virus, Mengovirus, Middelburg virus, milkers nodule virus, mink enteritis virus, minute virus of mice, MLV related virus, MM virus, Mokola virus, Molluscipoxvirus, Molluscum contagiosum virus, monkey B virus, monkeypox virus, Mononegavirales, Morbillivirus, Mount Elgon bat virus, mouse cytomegalovirus, mouse encephalomyelitis virus, mouse hepatitis virus, mouse K
virus, mouse leukemia virus, mouse mammary tumor virus, mouse minute virus, mouse pneumonia virus, mouse poliomyelitis virus, mouse polyomavirus, mouse sarcoma virus, mousepox virus, Mozambique virus, Mucambo virus, mucosal disease virus, mumps virus, murid betaherpesvirus 1, murid cytomegalovirus 2, murine cytomegalovirus group, murine encephalomyelitis virus, murine hepatitis virus, murine leukemia virus, murine nodule inducing virus, murine polyomavirus, murine sarcoma virus, Muromegalovirus, Murray Valley encephalitis virus, myxoma virus, Myxovirus, Myxovirus multiforme, Myxovirus parotitidis, Nairobi sheep disease virus, Nairovirus, Nanirnavirus, Nariva virus, Ndumo virus, Neethling virus, Nelson Bay virus, neurotropic virus, New World Arenavirus, newborn pneumonitis virus, Newcastle disease virus, Nipah virus, noncytopathogenic virus, Norwalk virus, nuclear polyhedrosis virus (NPV), nipple neck virus, O'nyong'nyong virus, Ockelbo virus, oncogenic virus, oncogenic viruslike particle, oncornavirus, Orbivirus, Orf virus, Oropouche virus, Orthohepadnavirus, Orthomyxovirus, Orthopoxvirus, Orthoreovirus, Orungo, ovine papillomavirus, ovine catarrhal fever virus, owl monkey herpesvirus, Palyam virus, Papillomavirus, Papillomavirus sylvilagi, Papovavirus, parainfluenza virus, parainfluenza virus type 1, parainfluenza virus type 2, parainfluenza virus type 3, parainfluenza virus type 4, Paramyxovirus, Parapoxvirus, paravaccinia virus, Parvovirus, Parvovirus B19, parvovirus group, Pestivirus. Phlebovirus, phocine distemper virus, Picodnavirus, Picornavirus, pig cytomegalovirus-pigeonpox virus, Piry virus, Pixuna virus, pneumonia virus of mice, Pneumovirus, poliomyelitis virus, poliovirus, Polydnavirus, polyhedral virus, poly oma virus, Polyomavirus, Polyomavirus bovis, Polyomavirus cercopitheci, Polyomavirus hominis 2, Polyomavirus maccacae 1, Polyomavirus muris 1, Polyomavirus muris 2, Polyomavirus papionis 1, Polyomavirus papionis 2, Polyomavirus sylvilagi, Pongine herpesvirus 1, porcine epidemic diarrhea virus, porcine hemagglutinating encephalomyelitis virus, porcine parvovirus, porcine transmissible gastroenteritis virus, porcine type C virus, pox virus, poxvirus, poxvirus variolae, Prospect Hill virus, Provirus, pseudocowpox virus, pseudorabies virus, psittacinepox virus, quailpox virus, rabbit fibroma virus, rabbit kidney vaculolating virus, rabbit papillomavirus, rabies
-17-virus, raccoon parvovirus, raccoonpox virus, Ranikhet virus, rat cytomegalovirus, rat parvovirus, rat virus, Rauscher's virus, recombinant vaccinia virus, recombinant virus, reovirus, reovirus 1, reovirus 2, reovirus 3, reptilian type C virus, respiratory infection virus, respiratory syncytial virus, respiratory virus, reticuloendotheliosis virus, Rhabdovirus, Rhabdovirus carpia, Rhadinovirus, Rhinovirus, Rhizidiovirus, Rift Valley fever virus, Riley's virus, rinderpest virus, RNA
tumor virus, Ross River virus, Rotavirus, rougeole virus, Rous sarcoma virus, rubella virus, rubeola virus, Rubivirus, Russian autumn encephalitis virus, SA 11 simian virus, SA2 virus, S abi a virus, Sagiyama virus, Saimirine herpesvirus 1, salivary gland virus, sandfly fever virus group, Sandjimba virus, SARS virus, SDAV
(sialodacryoadenitis virus), sealpox virus, Semliki Forest Virus, Seoul virus.
sheeppox virus, Shope fibroma virus, Shope papilloma virus, simian foamy virus, simian hepatitis A
virus, simian human immunodeficiency virus, simian immunodeficiency virus, simian parainfluenza virus, simian T cell lymphotrophic virus, simian virus, simian virus 40, Simplexvirus, Sin Nombre virus, Sindbis virus, smallpox virus, South American hemorrhagic fever viruses, sparrowpox virus, Spumavirus, squirrel fibroma virus, squirrel monkey retrovirus, SSV 1 virus group, STLV (simian T
lymphotropic virus) type I, STLV (simian T lymphotropic virus) type II, STLV (simian T
lymphotropic virus) type III, stomatitis papulosa virus, submaxillary virus, suid alphaherpesvirus 1, suid herpesvirus 2, Suipoxvirus, swamp fever virus, swinepox virus, Swiss mouse leukemia virus, TAC virus, Tacaribe complex virus, Tacaribe virus, Tanapox virus, Taterapox virus, Tench reovirus, Theiler's encephalomyelitis virus, Theiler's virus, Thogoto virus, Thottapalayam virus, Tick borne encephalitis virus, Tioman virus, Togavirus, Torovirus, tumor virus, Tupaia virus, turkey rhinotracheitis virus, turkeypox virus, type C retroviruses, type D oncovirus, type D retrovirus group, ulcerative disease rhabdovirus, Una virus, Uukuniemi virus group, vaccinia virus, vacuolating virus, varicella zoster virus, Varicellovirus, Varicola virus, variola major virus, variola virus, Vasin Gishu disease virus, VEE virus, Venezuelan equine encephalitis virus, Venezuelan equine encephalomyelitis virus, Venezuelan hemorrhagic fever virus, vesicular stomatitis virus, Vesiculovirus, Vilyuisk virus, viper retrovirus, viral haemorrhagic septicemia virus, Visna Maedi virus, Visna virus, volepox virus, VSV
(vesicular stomatitis virus), Wallal virus, Warrego virus, wart virus, WEE
virus, West Nile virus, western equine encephalitis virus, western equine encephalomyelitis virus, Whataroa virus, Winter Vomiting Virus, woodchuck hepatitis B virus, woolly monkey sarcoma virus, wound tumor virus, WRSV virus, Yaba monkey tumor virus, Yaba virus, Yatapoxvirus, yellow fever virus, or the Yug Bogdanovac virus. In some embodiments, the infectious disease is caused by the coronavirus.
[0052] The disease may be a cancer. In some further instances, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, and liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Cell lymphomas), Hodgkin's lymphoma, leukemia (including MDS, AML, ALL, ATLL and CML), or multiple myeloma. As used herein, the term "cancer"
refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g. humans), including leukemia, carcinomas and sarcomas. Exemplary cancers that may be treated with a compound or method provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer, lung cancer, and cancer of the head. Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, Medulloblastoma, colorectal cancer, pancreatic cancer. Additional examples include, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.
[0053] The term "leukemia" refers broadly to progressive, malignant diseases of the blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved;
myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocy tic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.
[0054] The term "sarcoma generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma. liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B
cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.
[0055] The term "melanoma" is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.
[0056] The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound or method provided herein include, for example, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, I enticular carcinoma, carcinoma lenti cul are, lipomatous carcinoma, lymphoepitheli al carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.
[0057] As used herein, the term "autoimmune disease" refers to a disease or condition in which a subject's immune system has an aberrant immune response against a substance that does not normally elicit an immune response in a healthy subject. Examples of autoimmune diseases that may be treated with a compound, pharmaceutical composition, or method described herein include Acute Disseminated Encephalomyelitis (ADEM), Acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome (AP S), Autoimmune angi oedema, Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmune hepatitis, Autoimmune hyperlipidemia, Autoimmune immunodeficiency, Autoimmune inner ear disease (A1ED), Autoimmune myocarditis_ Autoimmune oophoritis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic purpura (ATP), Autoimmune thyroid disease, Autoimmune urticaria, Axonal or neuronal neuropathies, Balo disease, Behcet's disease, Bullous pemphigoid, Cardiomyopathy, Castleman disease, Celiac disease, Chagas disease, Chronic fatigue syndrome, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal ostomyelitis (CRM0), Churg-Strauss syndrome, Cicatricial pemphigoid/benign mucosal pemphigoid, Crohn's disease, Cogans syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST disease, Essential mixed cryoglobulinemia, Demyelinating neuropathies, Dermatitis herpetiformis, Dermatomyositis, Devic's disease (neuromyelitis optica), Discoid lupus, Dressler's syndrome, Endometriosis, Eosinophilic esophagitis, Eosinophilic fasciitis, Erythema nodosum, Experimental allergic encephalomyelitis, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, Goodpasture's syndrome, Granulomatosis with Polyangiitis (GPA) (formerly called Wegener's Granulomatosis), Graves' disease, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura, Herpes gestationis, Hypogammaglobulinemi a, Idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, Immunoregulatory lipoproteins, Inclusion body myositis, Interstitial cystitis, Juvenile arthritis, Juvenile diabetes (Type 1 diabetes). Juvenile mvositis, Kawasaki syndrome, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus (SLE), Lyme disease, chronic, Meniere's disease, Microscopic polyangiitis, Mixed connective tissue disease (MC'TD), Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica (Devic's), Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus), Paraneoplastic cerebellar degeneration, Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Parsonnage-Turner syndrome, Pars planitis (peripheral uveitis), Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia, POEMS
syndrome, Polyarteritis nodosa, Type I, II, & III autoimmune polyglandular syndromes, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Progesterone dermatitis, Primary biliary cirrhosis, Primary sclerosing cholangitis, Psoriasis, Psoriatic arthritis, Idiopathic pulmonary fibrosis, Pvoderma gangrenosum, Pure red cell aplasia, Raynauds phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Reiter's syndrome, Relapsing poly chondritis, Restless legs syndrome, Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren's syndrome, Sperm &
testicular autoimmunity, Stiff person syndrome, Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia, Takayasu's arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (HP), Tolosa-Hunt syndrome, Transverse myelitis_ Type 1 diabetes, Ulcerative colitis, Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vesiculobullous dermatosis, Vitiligo, or Wegener's granulomatosis (i.e., Granulomatosis with Polyangiitis (GPA). In some embodiments, the autoimmune disease is not asthma.
[0058] As used herein, the term "inflammatory disease" refers to a disease or condition characterized by aberrant inflammation (e.g. an increased level of inflammation compared to a control such as a healthy person not suffering from a disease). Examples of inflammatory diseases include traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison's disease, Vitiligo,asthma, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystiti s, ath ero scl erosi s, and atopi c dermatitis.
[0059] The terms "treating" or "treatment" refer to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. The term "treating" and conjugations thereof, may include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing.
[0060] "Treating- or "treatment- as used herein (and as well-understood in the art) also broadly includes any approach for obtaining beneficial or desired results in a subject's condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease's transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable. In other words, "treatment" as used herein includes any cure, amelioration, or prevention of a disease. Treatment may prevent the disease from occurring;
inhibit the disease's spread; relieve the disease's symptoms (e.g., ocular pain, seeing halos around lights, red eye, very high intraocular pressure), fully or partially remove the disease's underlying cause, shorten a disease's duration, or do a combination of these things.
[0061] "Treating" and "treatment" as used herein include prophylactic treatment. Treatment methods include administering to a subject a therapeutically effective amount of a compound described herein.
The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of the compound, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compositions are administered to the subject in an amount and duration sufficient to treat the patient.
[0062] The terms "prevent," "preventing," and "prevention" refer to a decrease in the occurrence of disease symptoms in a patient. The preventing or prevention may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur absent treatment. In embodiments, prevent refers to slowing the progression of the disease, disorder or condition or inhibiting progression thereof to a harmful or otherwise undesired state.
[0063] "Patient" or "subject in need thereof" refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals including, but not limited to, fish and birds.F"effec In some embodiments, a patient is human.
[0064] Treatment, as referred to herein, also refers to the systemic delivery of the compounds disclosed herein to any type of plant, including trees, shrubs, flowering plants, foliage plants, house plants, groundcover and grass, and agronomic plants (including crops of agronomic plants).
[0065] An "effective amount- is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). An example of an -effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a -therapeutically effective amount." A "reduction- of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A
"prophylactically effective amount- of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An "activity decreasing amount," as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A "function disrupting amount," as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and irechnology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). The therapeutically effective amount can be ascertained by measuring relevant physiological effects, and it can be adjusted in connection with the dosing regimen and diagnostic analysis of the subject's condition, and the like. By way of example, measurement of the serum level of a compound of Formula (1) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof (or, e.g., a metabolite thereof) at a particular time post-administration may be indicative of whether a therapeutically effective amount has been administered.
[0066] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.
100671 As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
Adjusting the dose to achieve maximal therapeutic window efficacy or toxicity in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
[0068] The term -therapeutically effective amount," as used herein, refers to that amount of the therapeutic agent sufficient to ameliorate the disorder, as described above.
For example, for the given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy can also be expressed as --fold" increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control.
[0069] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present disclosure should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.
Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
[0070] As used herein, the term -administering- means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By "co-administer- it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g., chemotherapeutic agent). The compound of the disclosure can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent).
Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). The compositions of the present disclosure can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols_ Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. The compositions of the present disclosure may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates.
These components are discussed in greater detail in U.S. Pat. Nos. 4.911,920; 5,403,841; 5,212,162;
and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.
The compositions of the present disclosure can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, I
Btomater Sci. Polym. Ed.
7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res.
12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, I Pharm.
Pharmacol. 49:669-674, 1997). In another embodiment, the formulations of the compositions of the present disclosure can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing receptor ligands attached to the liposome, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries receptor ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present disclosure into the target cells in vivo. (See, e.g., Al-Muhammed, I
Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. I Hosp.
Pharm. 46:1576-1587, 1989). The compositions of the present disclosure can also be delivered as nanoparticles.
[0071] By "co-administer" it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the disclosure can be administered alone or can be coadministered to the patient.
Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). The compositions of the present disclosure can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
[0072] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.
[0073] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
[0074] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present disclosure should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.
[0075] Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
[0076] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.
[0077] The compounds described herein can be used for treating an infectious disease. In some embodiments, the compounds described herein are used as an anti-coagulant. The compounds described herein can be used in combination with one another, with other active agents known to be useful in treating cancer (e.g., colon cancer), cardiovascular disease, metabolic disease, immune or inflammatory disease or disorder, or an infectious disease or disorder.
[0078] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 2 days, 4 days, 1 week or 1 month of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and/or adjunctive agents may be linked or conjugated to one another. In some embodiments, the compounds described herein may be combined with treatments for cancer or infections (e.g., fungal infections, bacterial infections, viral infections, etc.) [0079] A "cell" as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaryotic cells.
Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.
[0080] "Control- or "control experiment- is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples).
[0081] The phrase -in a sufficient amount to effect a change" means that there is a detectable difference between a level of an indicator measured before (e.g., a baseline level) and after administration of a particular therapy. Indicators include any objective parameter (e.g., serum concentration) or subjective parameter (e.g., a subject's feeling of well-being).
[0082] -Substantially pure- indicates that a component makes up greater than about 50% of the total content of the composition, and typically greater than about 60% of the total polypeptide content.
More typically, "substantially pure" refers to compositions in which at least 75%, at least 85%, at least 90% or more of the total composition is the component of interest. In some cases, the polypeptide will make up greater than about 90%, or greater than about 95% of the total content of the composition (percentage in a weight per weight basis).
[0083] "Capsaicin" as used herein is also referred to as (6E)-N4(4-Hydroxy-3-methoxyphenyOmethy11-8-methylnon-6-enamide, (E)-N-(4-Hydroxy-3-methoxybenzy1)-methylnon-6-enamide, 8-Methyl-N-vanillyl-trans-6-nonenamide, trans-8-Methyl-N-vanillylnon-6-enamide, (E)-Capsaicin, Capsicine, Capsicin, and/or CPS and has the chemical structure:
1-10leo [0084] In some embodiments, the compound of structural Formula (I), is capsaicin or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
Compositions [0085] In an aspect, provided herein is a composition, comprising:
(i) a compound of structural Formula (I):
(R1)2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, -0R1A, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1-6 alkyl; and R1A is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
(ii) at least one additional therapeutic agent selected from:
a fatty acid amide hydrolase (FAAH) receptor inhibitor, and a specialized pro-resolving mediator (SPM), or a combination thereof; and (iii) at least one excipient.
[0086] In an aspect, provided herein is a composition, consisting essentially of:
(i) a compound of structural Formula (I):
(R1)2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨ORIA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1-6 alkyl; and RIA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
(ii) a transient receptor potential cation channel subfamily V member 1 (TrpV1) modulator; and (iii) at least one excipient.
[0087] In an aspect, provided herein is a composition, consisting essentially of:
(i) capsaicin, or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof;
(ii) a transient receptor potential cation channel subfamily V member 1 (TrpV1) modulator; and (iii) at least one excipient [0088] In an aspect, provided herein is a composition, consisting essentially of:
(i) capsaicin, or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof;
(ii) oleic acid; and (iii) at least one excipient.
100891 In an aspect, provided herein is a composition, comprising:
(i) a compound of structural Formula (I):
(R1)1-12 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨ORIA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1-6 alkyl; and RIA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
(ii) a transient receptor potential cation channel subfamily V member 1 (TrpV1) modulator; and (iii) at least one excipient, wherein when the compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is capsaicin, then the capsaicin is present in the composition in an amount in a range of 0. 1%(w/v) to about 50%
(w/v).
[0090] In an aspect, provided herein is a composition, comprising:
(i) a compound of structural Formula (I):
(R1)2 = X - - R2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨ORIA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1_6 alkyl; and RIA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONI-12, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and (ii) at least one additional therapeutic agent selected from:
a fatty acid amide hydrolase (FAAH) receptor inhibitor, and a specialized pro-resolving mediator (SPM), or a combination thereof.
[0091] In an aspect, provided herein is a composition, consisting essentially of:
(i) a compound of structural Formula (I):
(R1)112 410 X '.5 R2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨ORIA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1-6 alkyl; and RIA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and (ii) a transient receptor potential cation channel subfamily V member 1 (TrpV1) modulator.
100921 In an aspect, provided herein is a composition, consisting essentially of:
(i) capsai ci n, or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof; and (ii) a transient receptor potential cation channel subfamily V member 1 (TrpV1) modulator.
100931 In an aspect, provided herein is a composition, consisting essentially of:
(i) capsaicin, or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof; and (ii) oleic acid.
[0094] In an aspect, provided herein is a composition, comprising:
(i) a compound of structural Formula (I):
(R1)2 ni 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨010A, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R' is hydrogen or substituted or unsubstituted C 1 -6 alkyl; and RIA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and (ii) a transient receptor potential cation channel subfamily V member 1 (TrpV1) modulator;
wherein when the compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is capsaicin, then the capsaicin is present in the composition in an amount in a range of 0.1%(w/v) to about 50%
(w/v).
[0095] In some embodiments, when the compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is capsaicin, gingerols, piperines, or shogaols, then the capsaicin, gingerols, piperines, or shogaols are present in the composition in an amount 0.1%(w/v) to about 50% (w/v). In some embodiments, when the compound of structural Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is capsaicin, guai acol , eugenol, Zingerone, ci yam i de, nonivamide, nuvanil, olvanil, NE-19550, NE-21610, or NE-28345, then the capsaicin, guaiacol, eugenol, Zingerone, civamide, nonivamide, nuvanil, olvanil, NE-19550, NE-21610, or NE-28345 are present in the composition in an amount 0.1%(w/v) to about 50% (w/v).
[0096] In an aspect, provided herein is a composition, comprising:
(i) a compound of structural Formula (I):
(R1)n2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨ORI4, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1-6 alkyl; and RIA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and (ii) a TrpV1 modulator;
wherein the compound of Formula (I), isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is not capsaicin; or wherein the TrpV1 modulator is not a fatty acid.
100971 In an aspect, provided herein is a composition, comprising:
(i) a compound of structural Formula (I):
(R1)2 = X R2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨ORI-, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1-6 alkyl; and RIP' is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
(ii) a TrpV1 modulator; and (iii) at least one excipient, wherein the compound of Formula (I), isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is not capsaicin; or wherein the TrpV1 modulator is not a fatty acid.
[0098] In some embodiments, the compound of Formula (I) is capsaicin. In some embodiments, the compound of Formula (I) is dihydrocapsaicin.
[0099] In some embodiments, the at least one TrpV1 modulator is a TrpV1 antagonist, a TrpV1 competitive agonist, or combination thereof.
[0100] In some embodiments, the at least one TrpV1 modulator is a triglyceride or spilanthol.
101011 In some embodiments, the at least one TrpV1 modulator is a fatty acid, triglyceride, or spilanthol.
[0102] In some embodiments, the fatty acid is a polyunsaturated fatty acid (PUFA).
[0103] In some embodiments, the fatty acid is a cannabinoid.
[0104] In some embodiments, the PUFA is anandamide.
[0105] In some embodiments, the PUFA is a cannabinoid.
[0106] In some embodiments, the fatty acid is an omega-9 fatty acid. In some embodiments, the fatty acid is an omega-3 fatty acid.
[0107] In some embodiments, the fatty acid is oleic acid or erucic acid.
[0108] In some embodiments, the at least one additional therapeutic agent is a FAAH receptor inhibitor.
101091 In some embodiments, the FAAH receptor inhibitor is SSR411298.
[0110] In some embodiments, the at least one additional therapeutic agent is a FAAH inhibitor.
[0111] In some embodiments, the FAAH inhibitor is a flavonoid. Exemplary flavonoids include, but are not limited to, myricetin, quercetin, kaempferol, luteolin, and apigenin.
In some embodiments, the FAAH inhibitor is kaempferol.
[0112] In some embodiments, the at least one additional therapeutic agent is an SPM.
[0113] In some embodiments, the SPM is maresin.
[0114] In some embodiments, the pharmaceutical composition is in a form for oral dosing or administration.
[0115] In some embodiments, the form is a suspension or a solution.
[0116] In some embodiments, the form is a solid dosage form.
101171 In some embodiments, the form is a tablet or a capsule.
[0118] In some embodiments, the pharmaceutical composition is in a form for inhalation, nebulization, or nasal delivery.
[0119] In some embodiments, the pharmaceutical composition is provided as an aerosol. In some embodiments, the pharmaceutical composition is provided as an inhalable aerosol. In some embodiments, the pharmaceutical composition is in a form of an electronic delivery system. In some embodiments, the pharmaceutical composition is a vaping device. In some embodiments, the pharmaceutical composition is provided as an e-cigarette.
[0120] In some embodiments, the pharmaceutical composition is in a form for inhalation administration or dosing by vaporizer.
[0121] In some embodiments, the pharmaceutical composition is in a form for parenteral administration or dosing.
101221 In some embodiments, the parenteral administration or dosing is injection, infusion, or implantation.
101231 In some embodiments, the injection is intravenous, intramuscular, subcutaneous, or intradermal.
[0124] In some embodiments, the pharmaceutical composition is in a form for dosing or administration by suppository.
[0125] In some embodiments, the pharmaceutical composition is in a form for cutaneous or transdermal administration.
[0126] In some embodiments, the pharmaceutical composition is in a form for sublingual or buccal administration.
[0127] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount less than about 10%, 5%, 2.5%, 1.0%, or 0.75% (w/v). In some embodiments, the compound of Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount in a range of about 0.5% to about 10%, about 0.5% to about 5%, about 1.0% to about 5%, or about 2.5% to about 4% (w/v).
[0128] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 0.1% (w/v).
[0129] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 1% (w/v).
[0130] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 10% (w/v).
[0131] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 20% (w/v).
[0132] In some embodiments, the compound of Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 30% (w/v).
[0133] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 40% (w/v).
[0134] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 0.1% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 1%
(w/v) to about 50%
(w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount less than about 10%, 5%, 2.5%, 1.0%, or 0.75% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount in a range of about 0.5% to about 10%, about 0.5% to about 5%, about 1.0% to about 5%, or about 2.5% to about 4% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 10% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt. solvate, or hydrate thereof is present in the composition in an amount of from about 15% (w/v) to about 50%
(w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 20% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 25% (w/v) to about 50%
(w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 30% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 35% (w/v) to about 50%
(w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 40% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 45% (w/v) to about 50%
(w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of about 10% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of about 15% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of about 20%
(w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of about 25% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of about 30% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of about 35%
(w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of about 40% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of about 45% (w/v). In some embodiments, the compound of Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of about 50%
(w/v).
[0135] In an aspect, provided herein is a composition, comprising:
(i) a compound of structural Formula (I):
( R.1) n2 = X R2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨ORIA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1-6 alkyl; and RIA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH,, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
(ii) a TrpV1 modulator; and (iii) at least one excipient, wherein the composition is formulated for dosing or delivery by enteral or parenteral administration [0136] In some embodiments, the composition is formulated as a liquid or a solid.
[0137] In some embodiments, the composition is formulated as a solid.
[0138] In some embodiments, the solid is a tablet, a capsule, a suppository, strip, or an implant.
101391 In some embodiments, the tablet is a dissolvable tablet or a bilayer tablet.
101401 In some embodiments, the strip is a dissolvable strip.
101411 In some embodiments, the composition is formulated as a liquid.
[0142] In some embodiments, the liquid is a solution, a suspension, an emulsion, a syrup, an elixir, a tincture, an ointment, a soft gel, an enema, foam, cream, lotion, or a gel.
[0143] In some embodiments, the composition is formulated for dosing or delivery by enteral administration.
[0144] In some embodiments, the enteral administration is oral or rectal administration.
[0145] In some embodiments, the composition is formulated for dosing or delivery by parenteral administration.
[0146] In some embodiments, the parenteral administration is sublingual administration, buccal administration, or administration by injection, infusion, implantation, or inhalation.
[0147] In an aspect, provided herein is a composition, comprising:
(i) a compound of structural Formula (1):
(R1) n2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨0RiA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1-6 alkyl; and RIA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
(ii) a TrpV1 modulator; and (iii) at least one excipient.
[0148] In some embodiments, the solid is a tablet, a capsule, a suppository, strip, or an implant.
[0149] In some embodiments, the tablet is a dissolvable tablet or a bilayer tablet.
101501 In some embodiments, the strip is a dissolvable strip.
101511 In an aspect, provided herein is a composition, comprising:
(i) a compound of structural Formula (I):
(R1)2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨ORIA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1_6 alkyl; and RiA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONE12, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
(ii) a TrpV1 modulator; and (iii) at least one excipient, wherein the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, and the TrpV1 modulator are released sequentially in any order or have different release profiles. In some embodiments, the co-formulated compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, and the TrpV1 modulator are administered sequentially. In some embodiments, the co-formulated compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, and the TrpV1 modulator are administered sequentially in a bilayer tablet. In some embodiments, the co-formulated compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, and the TrpV1 modulator have different release profiles, for example the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof or the TrpV1 modulator is released immediately and the other is an extended release.
101521 In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is released before the at least one additional therapeutic agent.
[0153] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is released after the at least one additional therapeutic agent.
[0154] In some embodiments, the solid is a tablet, a capsule, a suppository, strip, or an implant.
[0155] In some embodiments, the tablet is a dissolvable tablet or a bilayer tablet.
[0156] In some embodiments, the strip is a dissolvable strip.
[0157] In some embodiments, the compound of Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount less than about 10%, 5%, 2.5%, 1.0%, or 0.75% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount in a range of about 0.5% to about 10%, about 0.5% to about 5%, about 1.0% to about 5%, or about 2.5% to about 4% (w/v).
[0158] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 10% (w/v).
[0159] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 20% (w/v).
[0160] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 30% (w/v).
[0161] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 40% (w/v).
[0162] In some embodiments, the compound of Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 10% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 20% (w/v) to about 50%
(w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 30% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 40% (w/v) to about 50%
(w/v).
[0163] In some embodiments, the composition is a modified-release dosage form, a sustained-release dosage form, or a controlled-release dosage form.
[0164] In some embodiments, the composition is in modified-release dosage form.
[0165] In some embodiments, the modified-release dosage form is a delayed-release dosage form, an extended release dosage form, or a targeted release dosage form.
[0166] In some embodiments, the ratio of TrpV1 modulator to a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is about 1:1.
[0167] In some embodiments, the ratio of FAAH receptor inhibitor to a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is about 1:1.
[0168] In some embodiments, the ratio of SPM to a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is about 1:1.
[0169] In some embodiments, the composition is formulated as a pharmaceutical composition.
[0170] In some embodiments, the at least one excipient is at least one pharmaceutically acceptable excipient.
[0171] In some embodiments, the compound of structural Formula (I) has structural Formula (I-A):
R1.1 $0 R1.2--X
n1 0 n3 (I-A), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
1.1 ¨
_EC is hydrogen, halogen, ¨012.11A, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
T.1.2 I( is hydrogen, halogen, ¨0RI.2A, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and R1.1A and R1.2A are independently hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
101721 In some embodiments, It is CH3; and R'2 is OH.
a [0173] In some embodiments, X is 0. In some embodiments, X is NH. In some embodiments, = is a a double bond. In some embodiments, is a single bond. In some embodiments, n1 is 2. In some embodiments, n1 is 1. In some embodiments, n1 is 0. In some embodiments, R2 is unsubstituted alkyl. In some embodiments, R2 is ¨CH(CH3)2 or ¨CH3.
[0174] In some embodiments, the compound is at least one of:
H. HO
HO si HO
HO is HO
HO HO
is , or H0 si O
HO
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
[0175] In some embodiments, the compound is:
HO
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
[0176] In another aspect, provided herein is a supplement, comprising:
(i) a compound of structural Formula (I):
= x R2 ni 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨ORIA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1_6 alkyl; and A
KIis hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
(ii) at least one additional therapeutic agent selected from:
a fatty acid amide hydrolase (FAAH) receptor inhibitor, and a specialized pro-resolving mediator (SPM), or a combination thereof; and (iii) at least one excipient. In some embodiments, the supplement is in a form for oral dosing or administration (i . e. , ingestion).
[0177] In some embodiments, the compound of structural Formula (I) has structural Formula (I-A):
R1.1 Cr R1.2-' -.61 R2 X
n1 0 n3 (I-A), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
R" is hydrogen, halogen, WI-A, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R1.2 is hydrogen, halogen, ¨010.2A, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R11- and R12- are independently hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH,, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
[0178] In some embodiments, R" is CH3; and R12 is OH.
a [0179] In some embodiments, X is 0. In some embodiments, X is NH. In some embodiments, = is a a double bond. In some embodiments, is a single bond. In some embodiments, n1 is 2. In some embodiments, n1 is 1. In some embodiments, n1 is 0. In some embodiments, R2 is unsubstituted alkyl. In some embodiments, R2 is ¨CH(CH3)2 or ¨CH3.
[0180] In some embodiments, the compound is at least one of:
HO HO
HO HO el HO HO
HO
, or HO
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
[0181] In some embodiments, the compound is:
HO
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
[0182] In some embodiments, the at least one additional therapeutic agent is a TrpV1 modulator. In some embodiments, the at least one TrpV1 modulator is a partial agonist, antagonist, an inverse agonist, or combinations thereof. In some embodiments, the at least one TrpV1 modulator is a TrpV1 antagonist, a TrpV1 competitive agonist, or combination thereof.
[0183] Exemplary TrpV1 modulators include, but are not limited to, DHA
(docosahexaenoic acid), EPA (eicosapentaenoic acid), LNA (linolenic acid), LA (linoleic acid), petroselinic acid, or oleic acid, a-Linolenic acid, spilanthol, a FAHH receptor inhibitor, SSR411298, a maresin, a specialized proresolving mediators (SPM), anandamide, cannabinoids, oleoylethanolamide, olvanil, arvanil.
AM404, derivatives thereof, or combinations thereof.
[0184] In some embodiments, the at least one TrpV1 modulator is a partial agonist. Partial agonists comprise TrpV1 modulators that can activate the current through the ion channel. In some embodiments, the partial agonist comprises a fatty acid. In some embodiments, the partial agonist comprises a polyunsaturated fatty acid (PUFA). In some embodiments, the partial agonist comprises a n-3 PUFA. In some embodiments, the partial agonist comprises a n-6 PUFA. In some embodiments, the partial agonist comprises DHA (docosahexaenoic acid), EPA
(eicosapentaenoic acid), LNA (linolenic acid), LA (linoleic acid), or combinations thereof. In some embodiments, the partial agonist comprises a free fatty acid, ester, triglyceride, or combination thereof of DHA
(docosahexaenoic acid), EPA (eicosapentaenoic acid), LNA (linolenic acid), or LA (linoleic acid).
[0185] In some embodiments, the at least one TrpV1 modulator is an antagonist.
Antagonists comprise TrpV1 modulators that can inhibit the current evoked by an agonist.
In some embodiments, a partial agonist acts as an antagonist since by displacing an agonist in the same binding site. In some embodiments, the antagonist comprises a fatty acid. In some embodiments, the antagonist comprises a polyunsaturated fatty acid (PUFA). In some embodiments, the antagonist comprises a n-3 PUFA.
In some embodiments, the antagonist comprises a n-6 PUFA. In some embodiments, the antagonist comprises DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid), LNA
(linolenic acid), LA
(linoleic acid), petroselinic acid, oleic acid, or combinations thereof. In some embodiments, the antagonist comprises a free fatty acid, ester, triglyceride, or combination thereof of DHA
(docosahexaenoic acid), EPA (eicosapentaenoic acid), LNA (linolenic acid), LA
(linoleic acid), petroselinic acid, or oleic acid.
[0186] In some embodiments, the antagonist is a synthetic TrpV1 antagonist. In some embodiments, the TrpV1 antagonist does not cause hyperthermia. In some embodiments, the TrpV1 antagonist do not affect H+ activation of the channel. In some embodiments, the TrpV1 antagonist is PH
I
.N 0 N .
L
0 H r 1 0 I
,,,, t...- 'N 'eS- ri ii3O
,s, . .b F i ri , n"- N F ...."`" - -N' a H
I ,...- F F
---CI -F 0 N'"Igliv .F
n Os_s_f F .40 o F ¨F
o HN 'N C.
it. .
r...\ C
? \ , 1 NN'ir H
H
..---- CHNN. .="' '0 N=s,. ,...--. N. ,...--- ,or , 0 - ' 0 A
HO ,....,11 H
F
, 1 ,õ,...
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
[0187] In some embodiments, the at least one TrpV1 modulator is an inverse agonist. In some embodiments, the inverse agonist comprises a fatty acid. In some embodiments, the inverse agonist comprises a polyunsaturated fatty acid (PUFA). In some embodiments, the inverse agonist is anandamide. In some embodiments, the inverse agonist has a similar structure as anandamide. In some embodiments, the inverse agonist has a similar mechanism of action as anandamide. In some embodiments, the inverse agonist is a cannabinoid. Exemplary agents that have a similar structure, similar mechanism, or both include, but are not limited to, oleyethanolamide (OEA), olvanil, arvanil, and AM404.
[0188] In some embodiments, the at least one TrpV1 modulator is a fatty acid, triglyceride, or spilanthol.
[0189] In some embodiments, the fatty acid is a cannabinoid.
[0190] In some embodiments, the fatty acid is a polyunsaturated fatty acid (PUFA).
[0191] In some embodiments, the PUFA is anandamide.
[0192] In some embodiments, the PUFA is a cannabinoid.
[0193] In some embodiments, the fatty acid is an omega-9 fatty acid. In some embodiments, the fatty acid is an omega-3 fatty acid.
[0194] In some embodiments, the fatty acid is oleic acid or erucic acid.
101951 In some embodiments, the at least one additional therapeutic agent is a FAAH receptor inhibitor.
101961 In some embodiments, the FAAH receptor inhibitor is SSR411298.
[0197] In some embodiments, the at least one additional therapeutic agent is a FAAH inhibitor.
[0198] In some embodiments, the FAAH inhibitor is a flavonoid. Exemplary flavonoids include, but are not limited to, myricetin, quercetin, kaempferol, luteolin, and apigenin.
In some embodiments, the FAAH inhibitor is kaempferol.
[0199] In some embodiments, the at least one additional therapeutic agent is an SPM.
[0200] In some embodiments, the SPM is maresin.
[0201] In some embodiments, the supplement is in a form for oral dosing or administration. In some embodiments, the form is a suspension or a solution. In some embodiments, the form is a solid dosage form. In some embodiments, the solid dosage form is a tablet or a capsule.
[0202] In some embodiments, the supplement is in a form for inhalation, nebulization, or nasal delivery.
[0203] In some embodiments, the pharmaceutical composition is provided as an aerosol. In some embodiments, the pharmaceutical composition is provided as an inhalable aerosol. In some embodiments, the pharmaceutical composition is in a form of an electronic delivery system. In some embodiments, the pharmaceutical composition is a vaping device. In some embodiments, the pharmaceutical composition is provided as an e-cigarette.
[0204] In some embodiments, the supplement is in a form for inhalation administration or dosing by vaporizer.
[0205] In some embodiments, the supplement is in a form for parenteral administration or dosing.
[0206] In some embodiments, the administration or dosing is parenteral injection.
[0207] In some embodiments, the injection is intravenous, intramuscular, subcutaneous, or intradermal.
[0208] In some embodiments, the supplement is in a form for dosing or administration by suppository.
[0209] In some embodiments, the supplement is in a form for cutaneous or transdermal administration.
[0210] In some embodiments, the supplement is in a form for sublingual or buccal administration.
[0211] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount less than about 10%, 5%, 2.5%, 1.0%, or 0.75% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount in a range of about 0.5% to about 10%, about 0.5% to about 5%, about 1.0% to about 5%, or about 2.5% to about 4% (w/v).
102121 In some embodiments, the compound of Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 10% (w/v).
[0213] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 20% (w/v).
[0214] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 30% (w/v).
[0215] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 40% (w/v).
[0216] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 10% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 20% (w/v) to about 50%
(w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 30% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 40% (w/v) to about 50%
(w/v).
[0217] In some embodiments of the pharmaceutical compositions disclosed herein, the form is a suspension or a solution.
[0218] In some embodiments of the pharmaceutical compositions disclosed herein, the form is a tablet or a capsule.
[0219] In some embodiments of the pharmaceutical compositions disclosed herein, wherein the form is a tablet or a capsule, the tablet or capsule has an enteric coating.
[0220] In some embodiments of the pharmaceutical compositions disclosed herein, wherein the form is a tablet, the tablet is an osmotic floating tablet.
[0221] In some embodiments of the pharmaceutical compositions disclosed herein, wherein the form is a capsule, the capsule is a liquid-filled hard capsule.
[0222] In some embodiments of the pharmaceutical compositions disclosed herein, wherein the form is a capsule, the capsule is a soft gelatin capsule.
[0223] In some embodiments of the pharmaceutical compositions disclosed herein, the form is a modified-release dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the form is a modified-release dosage form, wherein the modified-release dosage form is a delayed-release dosage form, an extended-release (ER) dosage form, or a targeted-release dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the form is an extended-release (ER) dosage form, the ER dosage form is a sustained-release (SR) dosage form or controlled-release (CR) dosage form.
[0224] In some embodiments of the pharmaceutical compositions disclosed herein, the form is an I.V. (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is from about 3.5 to about 14. In some embodiments of the pharmaceutical compositions disclosed herein, the form is an I.V. (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is from about 5.0 to about 12. In some embodiments of the pharmaceutical compositions disclosed herein, the form is an I.V. (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition, wherein the form is an IV. dosage form, the pH is from about 5.5 to about 11. In some embodiments of the pharmaceutical composition, wherein the form is an I.V.
dosage form, the pH is about 3.5. In some embodiments of the pharmaceutical composition, wherein the form is an I. V. dosage form, the pH is about 4Ø In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 4.5. In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 5Ø In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 5.5. In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 6Ø In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 6.5. In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 7Ø In some embodiments of the pharmaceutical composition, wherein the form is an 1.V.
dosage form, the pH is about 7.5. In some embodiments of the pharmaceutical composition, wherein the form is an I.V.
dosage form, the pH is about 8Ø In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 8.5. In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 9Ø In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 9.5. In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 10Ø In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 10.5. In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 11Ø In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 11.5. In some embodiments of the pharmaceutical composition, wherein the form is an I.V.
dosage form, the pH is about 12Ø In some embodiments of the pharmaceutical composition, wherein the form is an 1.V.
dosage form, the pH is about 12.5. In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 13Ø In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 13.5. In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 14Ø
[0225] In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions are formulated for systemic delivery. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions are not formulated for local delivery. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions, when injected, result in a high level of systemic delivery or exposure without significant depot in the area of injection (i.e., do not provide a high local concentration of a compound of Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, and/or a TrpV1 modulator (e.g., TrpV1 inhibitor, TrpV1 antagonist, a TrpV1 competitive agonist.) In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions, when injected, result in a high level of systemic delivery or exposure and are not significantly retained in the skin.
[0226] In some embodiments of the pharmaceutical compositions disclosed herein, wherein the form is a suspension or a solution, the dosage form comprises a co-solvent.
[0227] In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form comprises a co-solvent, the co-solvent comprises PEG200, PEG300, PEG400, PEG600, propylene glycol, ethanol, polysorbate 20, polysorbate 80, cremephor, glycerin, benzyl alcohol, dimethylacetamide (DMA), N-methy1-2-pyr.rolidone (NMP), tert-butanol, or combinations thereof.
[0228] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form further comprises an oil.
[0229] In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form further comprises an oil, the oil comprises sesame oil, soybean oil, vegetable oil, poppyseed oil, safflower oil, or combinations thereof.
[0230] The compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof of the present disclosure may be in the form of compositions suitable for administration to a subject. In general, such compositions are "pharmaceutical compositions"
comprising a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients. In certain embodiments, the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof are present in a therapeutically acceptable amount. The pharmaceutical compositions may be used in the methods of the present disclosure; thus, for example, the pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice the therapeutic and prophylactic methods and uses described herein.
102311 The pharmaceutical compositions of the present disclosure can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein.
[0232] The pharmaceutical compositions containing the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof may be in a form suitable for oral use, for example, as tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads or elixirs.
Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents such as, for example, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets, capsules and the like contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture thereof. These excipients may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid;
binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
[0233] The tablets, capsules and the like suitable for oral administration may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by techniques known in the art to form osmotic therapeutic tablets for controlled release. Additional agents include biodegradable or biocompatible particles or a polymeric substance such as polyesters, polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides, polyglycolic acid, ethylene-vinylacetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide/glycolide copolymers, polylactide/glycolide copolymers, or ethylenevinylacetate copolymers in order to control delivery of an administered composition. For example, the oral agent can be entrapped in microcapsules prepared by coacervation techniques or by interfacial polymerization, by the use of hydroxymethyl cellulose or gelatin -microcapsules or poly(methylmethacrolate) microcapsules, respectively, or in a colloid drug delivery system. Colloidal dispersion systems include macromolecule complexes, nano-capsules, microspheres, microbeads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for the preparation of the above-mentioned formulations will be apparent to those skilled in the art.
[0234] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
[0235] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture thereof. Such excipients can be suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, for example a naturally-occurring phosphatide (e.g., lecithin), or condensation products of an alkylene oxide with fatty acids (e.g., polvoxv-ethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., for heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives.
[0236] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
[0237] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, and optionally one or more suspending agents and/or preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.
[0238] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example, liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example, gum acacia or gum tragacanth; naturally occurring phosphatides, for example, soybean, lecithin, and esters or partial esters derived from fatty acids;
hexitol anhydrides, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, for example, polyoxyethylene sorbi tan monooleate.
[0239] The pharmaceutical compositions typically comprise a therapeutically effective amount of a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically and physiologically acceptable formulation agents. Suitable pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methyl parabens, ethyl or n-propyl, p-hydroxybenzoate), emulsifying agents, suspending agents, dispersing agents, solvents, fillers, bulking agents, detergents, buffers, vehicles, diluents, and/or adjuvants. For example, a suitable vehicle may be physiological saline solution or citrate-buffered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art will readily recognize a variety of buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein.
Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. As an example, the buffer components can be water soluble materials such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Acceptable buffering agents include, for example, a Tris buffer; N-(2-Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES); 2-(N-Morpholino)ethanesulfonic acid (MES); 2-(N-Morpholino)ethanesulfonic acid sodium salt (MES); 3-(N-Morpholino)propanesulfonic acid (MOPS); and N-tris[Hydroxymethyllmethyl-3-aminopropanesulfonic acid (TAPS).
[0240] After a pharmaceutical composition has been formulated, it may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored either in a ready-to-use form, a lyophilized form requiring reconstitution prior to use, a liquid form requiring dilution prior to use, or other acceptable form. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, ampule, syringe, or autoinjector (similar to, e.g., an EpiPen0)), whereas a multi-use container (e.g., a multi-use vial) is provided in other embodiments.
[0241] Formulations can also include carriers to protect the composition against rapid degradation or elimination from the body, such as a controlled release formulation, including liposomes, hydrogels, prodrugs and microencapsulated delivery systems. For example, a time-delay material such as glyceryl monostearate or glyceryl stearate alone, or in combination with a wax, may be employed.
Any drug delivery apparatus may be used to deliver a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof, including implants (e.g., implantable pumps) and catheter systems, slow injection pumps and devices, all of which are well known to the skilled artisan.
[0242] Depot injections, which are generally administered subcutaneously or intramuscularly, may also be utilized to release the compound (e.g., a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof) disclosed herein over a defined period of time.
Depot injections are usually either solid- or oil-based and generally comprise at least one of the formulation components set forth herein. One of ordinary skill in the art is familiar with possible formulations and uses of depot injections.
[0243] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents mentioned herein.
The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butane diol.
Acceptable diluents, solvents and dispersion media that may be employed include water, Ringer's solution, isotonic sodium chloride solution, Cremophor EL (BASF, Parsippany, NJ) or phosphate buffered saline (PBS), ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium; for this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides. Moreover, fatty acids, such as oleic acid, find use in the preparation of injectables. Prolonged absorption of particular injectable formulations can be achieved by including an agent that delays absorption (e.g., aluminum monostearate or gelatin).
[0244] The present disclosure contemplates the administration of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof in the form of suppositories for rectal administration. The suppositories can be prepared by mixing the drug with a suitable non-irritating excipient, which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter and polyethylene glycols.
[0245] The compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof may be in the form of any other suitable pharmaceutical composition (e.g., sprays for nasal or inhalation use) currently known or developed in the future Methods of Use [0246] In an aspect, provided herein is a method of inhibiting mitochondrial complex I, comprising contacting the mitochondrial complex 1 with a compound of structural Formula (1):
(R1)2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
R' is independently hydrogen, halogen, ¨OR' A, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1-6 alkyl; and RiA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONW, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
[0247] In some embodiments, the compound of structural Formula I has the structure:
HO
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
[0248] In some embodiments, at least 10 viM of a compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used in the method of inhibiting mitochondrial complex I. In some embodiments, at least 15 p.M of a compound of structural Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used in the method of inhibiting mitochondrial complex I. In some embodiments, at least 20 p.M of a compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used in the method of inhibiting mitochondrial complex I. In some embodiments, at least 25 "AM of a compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used in the method of inhibiting mitochondrial complex I. In some embodiments, at least 30 uM of a compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used in the method of inhibiting mitochondrial complex I. In some embodiments, at least 35 1,04 of a compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used in the method of inhibiting mitochondri al complex I. In some embodiments, at least 40 uM of a compound of structural Formula (I), or an isotopic van i ant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used in the method of inhibiting mitochondrial complex I. In some embodiments, at least 45 uM of a compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used in the method of inhibiting mitochondrial complex I. In some embodiments, at least 45 uM of a compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used in the method of inhibiting mitochondrial complex I. In some embodiments, at least 50 uM of a compound of structural Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used in the method of inhibiting mitochondrial complex I.
[0249] In an aspect, provided herein is a method of a method of treating and/or preventing a capsaicin-responsive disease or disorder, comprising administering to a subject in need thereof a pharmaceutical composition or a supplement (e.g., a nutritional supplement) as disclosed herein.
[0250] In some embodiments, the disease or disorder is a cell proliferative disease, obesity, diabetes, a bacterial infection, a cardiovascular disease, a neurodegenerative disease or disorder, an inflammatory disease or disorder, a comorbidity, an autoimmune disease, hypercholesterolemia or a mood disorder. In some embodiments, the disease or disorder is an infectious disease or disorder (e.g., influenza or coronavirus). In some embodiments, the disease or disorder is a coagulant disease or disorder.
[0251] In some embodiments, the mood disorder is depression. In some embodiments, the inflammatory disease or disorder is rheumatoid arthritis. In some embodiments, the cell proliferative disease is a cancer. In some embodiments, the disorder is diabetes or obesity.
In some embodiments, the comorbidity is chronic kidney disease, stroke, congestive heart failure, dementia, schizophrenia, hepatitis, autism spectrum disorder, HIV, or a combination thereof.
[0252] In some embodiments, the supplements disclosed herein are for use in the treatment of a capsaicin-responsive disease or disorder.
[0253] In some embodiments, the supplements disclosed herein are for use in the treatment of obesity, diabetes, a bacterial infection, a cardiovascular disease, a neurodegenerative disease or disorder, an inflammatory disease or disorder, a comorbidity, an autoimmune disease, hypercholesterolemia or a mood disorder. In some embodiments, the supplements disclosed herein are used as an anti-coagulant. In some embodiments, the supplements disclosed herein are used for supporting the cognitive health of a human. In some embodiments, the supplements disclosed herein are used for supporting clarity and/or concentration of a human. In some embodiments, the supplements disclosed herein are used for promoting the longevity of a human.
In some embodiments, the supplements disclosed herein are used for boosting alertness or wakefulness of a human. In some embodiments, the supplements disclosed herein are used for supporting a healthy weight in a human. In some embodiments, the supplements disclosed herein are used for promoting the microbiome health of a human. In some embodiments, the supplements disclosed herein are used muscle energetic enhancers of a human.
[0254] In some embodiments, the mood disorder is depression. In some embodiments, the inflammatory disease or disorder is rheumatoid arthritis. In some embodiments, the cell proliferative disease is a cancer. In some embodiments, the disorder is diabetes or obesity.
[0255] In some embodiments, administration of the pharmaceutical compositions or supplements disclosed herein reduces fibrosis. In some embodiments, administration of the pharmaceutical composition or supplements disclosed herein decreases hepatic steatosis. In some embodiments, administration of the pharmaceutical composition or supplements disclosed herein decreases stellate cell activation. In some embodiments, administration of the pharmaceutical composition or supplements disclosed herein reduces body fat. In some embodiments, administration of the pharmaceutical composition or supplements disclosed herein reduces the percent of body fat as compared to body weight. In some embodiments, administration of the pharmaceutical composition or supplements disclosed herein decreases glucose levels. In some embodiments, administration of the pharmaceutical composition or supplements disclosed herein decreases fasting glucose levels. In some embodiments, administration of the pharmaceutical composition or supplements disclosed herein reduces capasacinoid-induced TRPV1 signaling. In some embodiments, the reduction is by at least or about 0.5X, 1.0X, 1.5X, 2.0X, 2.5X, 3.0X, 5X, 10X, or more than 10X.
[0256] In an aspect, provided herein is a method of treating or preventing a capsaicin-responsive disease or disorder, comprising administering to a subject in need thereof:
(i) a compound of structural Formula (I):
n1 o n3 (T), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨ORI", substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is substituted or unsubstituted C1-6 alkyl; and RiA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroallcyl; and (ii) at least one additional therapeutic agent selected from:
a transient receptor potential cation channel subfamily V member 1 (TrpV1) modulator, a fatty acid amide hydrolase (FAAH) receptor inhibitor; and a specialized pro-resolving mediator (SPM), or a combination thereof, wherein when the TrpV1 modulator is a fatty acid, then the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, and the TrpV1 modulator are each individually formulated.
102571 In some embodiments, R" is CH3; and R1.2 is OH.
a [0258] In some embodiments, X is 0. In some embodiments, X is NH. In some embodiments, = is a a double bond. In some embodiments, = is a single bond. In some embodiments, n1 is 2. In some embodiments, n1 is 1. In some embodiments, n1 is 0. In some embodiments, R2 is unsubstituted alkyl. In some embodiments, R2 is ¨CH(CH3)2 or ¨CH3.
[0259] In some embodiments, the compound is at least one of:
HO HO
HO HO
HO HO =
HO HO
HO si , or HO Is or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
[0260] In some embodiments, the compound is:
HO
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
[0261] In some embodiments, the TrpV1 modulator is derived from a foodstuff, foodstuff extract, a fruit extract, a vegetable extract, and/or a plant extract including but not limited to almonds, avocado, and/or olive oil.
[0262] In an aspect, provided herein is a method of treating a capsaicin-responsive disease or disorder, comprising subjecting a patient in need thereof to cryotherapy and administering a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
[0263] In an aspect, provided herein is a method of treating a capsaicin-responsive disease or disorder, comprising to a subject in need thereof a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, and milk, or a milk-derived product including but not limited to casein. In an aspect, provided herein is a method of treating a capsaicin-responsive disease or disorder, comprising to a subject in need thereof a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, and peanuts, or a peanut-derived product including but not limited to peanut butter.
[0264] In some embodiments, the at least one additional therapeutic agent is a TrpV1 modulator.
[0265] In some embodiments, the TrpV1 modulator is a TrpV1 antagonist, a TrpV1 competitive agonist, or combination thereof.
[0266] In some embodiments, the TrpV1 modulator is a fatty acid triglyceride, or spilanthol.
[0267] In some embodiments, the fatty acid is a cannabinoid.
[0268] In some embodiments, the fatty acid is a polyunsaturated fatty acid (PUFA).
[0269] In some embodiments, the PUFA is anandamide.
[0270] In some embodiments, the PUFA is a cannabinoid.
[0271] In some embodiments, the fatty acid is an omega-9 fatty acid. In some embodiments, the fatty acid is an omega-3 fatty acid.
[0272] In some embodiments, the fatty acid is oleic acid or erucic acid. In some embodiments, the fatty acid is oleic acid.
[0273] In some embodiments, the fatty acid is eicosapentanenoic acid (EPA). In some embodiments the fatty acid is docosahexaenoic acid (DHA).
102741 In some embodiments, the at least one additional therapeutic agent is a FAAH receptor inhibitor.
102751 In some embodiments, the FAAH receptor inhibitor is SSR411298.
[0276] In some embodiments, the at least one additional therapeutic agent is a FAAH inhibitor.
[0277] In some embodiments, the FAAH inhibitor is a flavonoid. Exemplary flavonoids include, but are not limited to, myricetin, quercetin, kaempferol, luteolin, and apigenin.
In some embodiments, the FAAH inhibitor is kaempferol.
[0278] In some embodiments, the at least one additional therapeutic agent is an SPM.
[0279] In some embodiments, the SPM is maresin.
[0280] In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally.
[0281] In some embodiments, the compound of structural Formula (1) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally via a suspension or solution.
[0282] In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally via a solid dosage form. In some embodiments, the solid dosage form is a tablet or capsule.
[0283] In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by inhalation, nebulization, or nasal delivery.
[0284] In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is provided as an aerosol. In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is provided as an inhalable aerosol. In some embodiments, the compound of structural Formula (1) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is in a form of an electronic delivery system. In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is administered using a vaping device. In some embodiments, the compound of structural Formula (1) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered using an e-cigarette.
[0285] In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by inhalation via a vaporizer.
[0286] In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered parenterally.
[0287] In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered via parenteral injection, infusion, or implantation.
[0288] In some embodiments, the parenteral injection is intravenous, intramuscular, subcutaneous, or intradermal.
[0289] In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered via a suppository.
[0290] In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered cutaneous or transdermal delivery.
[0291] In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by sublingual or buccal delivery.
[0292] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount less than about 10%, 5%, 2.5%, 1.0%, or 0.75% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount in a range of about 0.5% to about 10%, about 0.5% to about 5%, about 1.0% to about 5%, or about 2.5% to about 4% (w/v).
[0293] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 10% (w/v).
[0294] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 20% (w/v).
[0295] In some embodiments, the compound of Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 30% (w/v).
[0296] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 40% (w/v).
[0297] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 10% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 20% (w/v) to about 50%
(w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 30% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 40% (w/v) to about 50%
(w/v).
[0298] In some embodiments, the ratio of the therapeutic agent to a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is about 1:1. In some embodiments, the ratio of the therapeutic agent to a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is about 1.1:1. In some embodiments, the ratio of the therapeutic agent to a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is about 1.2:1. In some embodiments, the ratio of the therapeutic agent to a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is about 1.3:1. In some embodiments, the ratio of the therapeutic agent to a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is about 1.4:1. In some embodiments, the ratio of the therapeutic agent to a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is about 1.5:1.
[0299] In some embodiments, the disease or disorder is a cell proliferative disease, obesity, diabetes, a bacterial infection, a cardiovascular disease, a neurodegenerative disease or disorder, an inflammatory disease or disorder, a comorbidity, an autoimmune disease, hypercholesterolemia or a mood disorder. In some embodiments, the mood disorder is depression. In some embodiments, the inflammatory disease or disorder is rheumatoid arthritis. In some embodiments, the cell proliferative disease is a cancer. In some embodiments, the disorder is diabetes or obesity.
[0300] In some embodiments, the compound of Formula (1), or a pharmaceutically acceptable salt thereof, and the at least one additional therapeutic agent are administered simultaneously, approximately simultaneously, or sequentially, in any order.
[0301] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the at least one additional therapeutic agent are administered simultaneously or approximately simultaneously.
[0302] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the at least one additional therapeutic agent are administered sequentially.
[0303] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is released before the at least one additional therapeutic agent.
[0304] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is released after the at least one additional therapeutic agent [0305] In some embodiments of the methods described herein, the compound of Formula I, or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof, is administered to the subject daily.
[0306] In some embodiments of the methods described herein, the compound of Formula I, or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof, is administered to the subject once per day, twice per day, three times per day, or four times per day.
[0307] In some embodiments of the methods described herein, the compound of Formula 1, or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof, is administered to the subject for a period of at least one week.
[0308] In some embodiments of the methods described herein, the compound of Formula I, or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof, is administered to the subject for a period of one week, two weeks, 6 weeks, 12 weeks, 24 weeks, 48 weeks, or 52 weeks.
Dosing [0309] In some embodiments, the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof pharmaceutical compositions described herein are provided at the maximum tolerated dose (MTD) for the compound of Formula (I). In other embodiments, the amount of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof pharmaceutical composition administered is from about 10% to about 90% of the maximum tolerated dose (MTD), from about 25% to about 75% of the MTD, or about 50% of the MTD. In some other embodiments, the amount of the compound of Formula (1) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof pharmaceutical compositions administered is from about 0.1%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or higher, or any range derivable therein, of the MTD for the compound of Formula (I). Percentage can be weight by weight or weight by volume.
[0310] In certain embodiments, in the treatment, prevention, or amelioration of one or more symptoms of the disorders, diseases, or conditions described herein, an appropriate dosage level of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof generally is ranging from about 1 to 8000 mg, from about 1 to about 1000 mg, from about 5 to about 1000 mg, from about 5 to about 800 mg, from about 5 to about 600 mg, from about 5 to about 500 mg or from about 50 to about 500 mg which can be administered in single or multiple doses. In certain embodiments, the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 240, about 250, about 260, about 270, about 275, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000, about 1200, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, about 2400, about 2500, about 2600, about 2800, about 3000, about 4000, about 5000, about 6000, about 7000, about 8000 mg, or any range derivable therein.
[0311] In certain embodiments, the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 275 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000, about 1200, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, about 2400, about 2500, about 2600, about 2800, about 3000, about 4000, about 5000, about 6000, about 7000, about 8000 mg mg/day.
103121 For oral administration, the pharmaceutical compositions provided herein can be formulated in the form of tablets or capsules containing from about 1.0 to about 1,000 mg of a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof, in one embodiment, 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg. about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, or about 2000 mg of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof for the symptomatic adjustment of the dosage to the patient to be treated.
[0313] In some embodiments, the compound of Formula (I) or a hydrate, solvate.
tautomer, or pharmaceutically acceptable salt thereof is administered in an amount of about or at most 1 mg/day, about 5 mg/day, about 10 mg/day, about 15 mg/day, about 20 mg/day, about 25 mg/day, about 30 mg/day, about 35 mg/day, about 40 mg/day, about 45 mg/day, about 50 mg/day, about 55 mg/day, about 60 mg/day, about 65 mg/day, about 70 mg/day, about 75 mg/day, about 80 mg/day, about 85 mg/day, about 90 mg/day, about 95 mg/day, about 100 mg/day, about 105 mg/day, about 110 mg/day, about 115 mg/day, about 120 mg/day, about 125 mg/day, about 130 mg/day, about 135 mg/day, about 140 mg/day, about 145 mg/day, about 150 mg/day, about 155 mg/day, about 160 mg/day, about 170 mg/day, about 180 mg/day, about 190 mg/day, about 200 mg/day, about 210 mg/day, about 220 mg/day, about 230 mg/day, about 240 mg/day, about 250 mg/day, about 260 mg/day, about 270 mg/day, about 280 mg/day, about 290 mg/day, about 300 mg/day, about 310 mg/day, about 320 mg/day, about 330 mg/day, about 340 mg/day, about 350 mg/day, about 360 mg/day, about 370 mg/day, about 380 mg/day, about 390 mg/day, about 400 mg/day, 410 mg/day, about 420 mg/day, about 430 mg/day, about 440 mg/day, about 450 mg/day, about 460 mg/day, about 470 mg/day, about 480 mg/day, about 490 mg/day, about 500 mg/day, about 510 mg/day, about 520 mg/day, about 530 mg/day, about 540 mg/day, about 550 mg/day, about 560 mg/day, about 570 mg/day, about 580 mg/day, about 590 mg/day, or about 600 mg/day. In some embodiments, the compound of Formula (I) is administered in a range of about 1 mg/day to about 20 mg/day, about 1 mg/day to about 50 mg/day about 1 mg/day to about 100 mg/day, about 10 mg/day to about 100 mg/day, about 50 mg/day to about 500 mg/day, about 50 mg/day to about 250 mg/day, about 100 mg/day to about 500 mg/day or about 100 mg/day to about 200 mg/day.
[0314] In some embodiments, the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof is derived from a natural source such that about or at most 1 mg/day, about 5 mg/day, about 10 mg/day, about 15 mg/day, about 20 mg/day, about 25 mg/day, about 30 mg/day, about 35 mg/day, about 40 mg/day, about 45 mg/day, about 50 mg/day, about 55 mg/day, about 60 mg/day, about 65 mg/day, about 70 mg/day, about 75 mg/day, about 80 mg/day, about 85 mg/day, about 90 mg/day, about 95 mg/day, about 100 mg/day, about 105 mg/day, about 110 mg/day, about 115 mg/day, about 120 mg/day, about 125 mg/day, about 130 mg/day, about 135 mg/day, about 140 mg/day, about 145 mg/day, about 150 mg/day, about 155 mg/day, about 160 mg/day, about 170 mg/day, about 180 mg/day, about 190 mg/day, about 200 mg/day, about 210 mg/day, about 220 mg/day, about 230 mg/day, about 240 mg/day, about 250 mg/day, about 260 mg/day, about 270 mg/day, about 280 mg/day, about 290 mg/day, about 300 mg/day, about 310 mg/day, about 320 mg/day, about 330 mg/day, about 340 mg/day, about 350 mg/day, about 360 mg/day, about 370 mg/day, about 380 mg/day, about 390 mg/day, about 400 mg/day, 410 mg/day, about 420 mg/day, about 430 mg/day, about 440 mg/day, about 450 mg/day, about 460 mg/day, about 470 mg/day, about 480 mg/day, about 490 mg/day, about 500 mg/day, about 510 mg/day, about 520 mg/day, about 530 mg/day, about 540 mg/day, about 550 mg/day, about 560 mg/day, about 570 mg/day, about 580 mg/day, about 590 mg/day, or about 600 mg/day Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof is administered. For example, Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof is derived from chili, cayenne pepper, red pepper, oleoresin red pepper, tomato, or combinations thereof In some embodiments, Formula (1) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof is derived from Capsicum Frutescens or Oleoresin Capsicum.
103151 In some embodiments, the natural source comprises at least or about 1 mg/g, about 5 mg/g, about 10 mg/g, about 15 mg/g, about 20 mg/g, about 25 mg/g, about 30 mg/g, about 35 mg/g, about 40 mg/g, about 45 mg/g, about 50 mg/g, about 55 mg/g, about 60 mg/g, about 65 mg/g, about 70 mg/g, about 75 mg/g, or about 80 mg/g of a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the natural source comprises at least or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than 95% of a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof.
[0316] In some embodiments, various heat units of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof is administered. In some embodiments, the compound of Formula (1) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof comprises a Scoville Heat Unit (SHU) of about 0 to about 16 M SHU. In some embodiments, the compound of Formula (1) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof comprises a Scoville Heat Unit (SHU) of at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, or more than 16 M SHU. SHU, in some embodiments, provides the amount of sugar water to dilute a volume of pepper extract. For example, 100 SHU indicates that 100 mL
of sugar water is needed to dilute 1 mL of pepper extract.
[0317] In certain embodiments, in the treatment, prevention, or amelioration of one or more symptoms of the disorders, diseases, or conditions described herein, an appropriate dosage level of the compound of oleic acid or a pharmaceutically acceptable salt thereof generally is ranging from about 1 to 12000 mg, from about 1000 to 12000 mg, about 2000 to 12000 mg, about 3000 to 12000 mg about 4000 to 12000 mg, about 5000 to 12000 mg, about 6000 to 12000 mg, about 1000 to 11000 mg, about 1000 to 10000 mg, about 1000 to 9000 mg, about 1000 to 8000 mg, or about 1000 to 7000 mg, which can be administered in single or multiple doses. In certain embodiments, the oleic acid or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000mg or any range derivable therein.
[0318] In certain embodiments, the oleic acid, or pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg_ about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 275 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000, about 1200, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, about 2400. about 2500, about 2600, about 2800, about 3000, about 4000, about 5000, about 6000, about 7000, about 8000 mg mg/day. 1000 to 12000mg, about 2000 to 12000 mg, about 3000 to 12000 mg about 4000 to 12000 mg, about 5000 to 12000 mg, about 6000 to 12000 mg, about 1000 to 11000 mg, about 1000 to 10000 mg, about 1000 to 9000 mg, about 1000 to 8000 mg, or about 1000 to 7000 mg, which can be administered in single or multiple doses. In certain embodiments, the oleic acid or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000mg or any range derivable therein.
[0319] For oral administration, the pharmaceutical compositions provided herein can be formulated in the form of tablets or capsules containing from about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000mg of the compound of oleic acid or a pharmaceutically acceptable salt thereof for the symptomatic adjustment of the dosage to the patient to be treated.
[0320] In some embodiments, the oleic acid, or pharmaceutically acceptable salt thereof is administered in an amount of about or at most about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000 mg or any range derivable therein. In some embodiments, the oleic acid is administered in a range of about 1000 to 12000 mg/day, about 2000 to 12000 mg/day, about 3000 to 12000 mg/day about 4000 to 12000 mg/day, about 5000 to 12000 mg/day, about 6000 to 12000 mg/day, about 1000 to 11000 mg/day, about 1000 to 10000 mg/day, about 1000 to 9000 mg/day, about 1000 to 8000 mg/day, or about 1000 to 7000 mg/day. In some embodiments, the oleic acid or pharmaceutically acceptable salt thereof is derived from a natural source such that about or at most about 1 mg/day, about 10 mg/day, about 50 mg/day, about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 800 mg/day, about 900 mg/day, about 1000 mg/day, about 1100 mg/day, about 1200 mg/day, about 1300 mg/day, about 1400 mg/day, about 1500 mg/day, about 1600 mg/day, about 1700 mg/day, about 1800 mg/day, about 1900 mg/day, about 2000 mg/day, about 2100 mg/day, about 2200 mg/day, about 2300 mg/day, about 2400 mg/day, about 2500 mg/day, about 2600 mg/day, about 2700 mg/day, about 2800 mg/day, about 2900 mg/day, about 3000 mg/day, about 3100 mg/day, about 3200 mg/day, about 3300 mg/day, about 3400 mg/day, about 3500 mg/day, about 3600 mg/day, about 3700 mg/day, about 3800 mg/day, about 3900 mg/day, about 4000 mg/day, about 4100 mg/day, about 4200 mg/day, about 4300 mg/day, about 4400 mg/day, about 4500 mg/day, about 4600 mg/day, about 4700 mg/day, about 4800 mg/day, about 4900 mg/day. about 5000 mg/day about 5100 mg/day, about 5200 mg/day, about 5300 mg/day, about 5400 mg/day_ about 5500 mg/day, about 5600 mg/day, about 5700 mg/day, about 5800 mg/day, about 5900 mg/day, about 6000 mg/day, about 6100 mg/day, about 6200 mg/day, about 6300 mg/day, about 6400 mg/day, about 6500 mg/day, about 6600 mg/day, about 6700 mg/day, about 6800 mg/day, about 6900 mg/day, about 7000 mg/day, about 7100 mg/day, about 7200 mg/day, about 7300 mg/day, about 7400 mg/day, about 7500 mg/day, about 7600 mg/day, about 7700 mg/day, about 7800 mg/day, about 7900 mg/day, about 8000 mg/day, about 8100 mg/day, about 8200 mg/day, about 8300 mg/day, about 8400 mg/day, about 8500 mg/day, about 8600 mg/day, about 8700 mg/day, about 8800 mg/day, about 8900 mg/day, about 9000 mg/day, about 9100 mg/day, about 9200 mg/day, about 9300 mg/day, about 9400 mg/day, about 9500 mg/day, about 9600 mg/day, about 9700 mg/day, about 9800 mg/day, about 9900 mg/day, or about 10000 mg/day, about 10100 mg/day, about 10200 mg/day, about 10300 mg/day, about 10400 mg/day, about 10500 mg/day, about 10600 mg/day, about 10700 mg/day, about 10800 mg/day, about 10900 mg/day, about 11000 mg/day about 11100 mg/day, about 11200 mg/day, about 11300 mg/day, about 11400 mg/day, about 11500 mg/day, about 11600 mg/day, about 11700 mg/day, about 11800 mg/day, about 11900 mg/day, or about 12000mg/day oleic acid or pharmaceutically acceptable salt thereof is administered.
[0321] In some embodiments, the natural source comprises at least or about 1 mg/g, about 5 mg/g, about 10 mg/g, about 15 mg/g, about 20 mg/g, about 25 mg/g, about 30 mg/g, about 35 mg/g, about 40 mg/g, about 45 mg/g, about 50 mg/g, about 55 mg/g, about 60 mg/g, about 65 mg/g, about 70 mg/g, about 75 mg/g, or about 80 mg/g of oleic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the natural source comprises at least or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than 95% of a compound of oleic acid or pharmaceutically acceptable salt thereof.
[0322] In certain embodiments, in the treatment, prevention, or amelioration of one or more symptoms of the disorders, diseases, or conditions described herein, an appropriate dosage level of the compound of EPA or a pharmaceutically acceptable salt thereof generally is ranging from about 1 to 12000 mg, from about 1000 to 12000mg, about 2000 to 12000 mg, about 3000 to 12000 mg about 4000 to 12000 mg, about 5000 to 12000 mg, about 6000 to 12000 mg, about 1000 to 11000 mg, about 1000 to 10000 mg, about 1000 to 9000 mg, about 1000 to 8000 mg, or about 1000 to 7000 mg, which can be administered in single or multiple doses. In certain embodiments, the EPA or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000mg or any range derivable therein.
[0323] In certain embodiments, the EPA, or pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 275 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000, about 1200, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, about 2400, about 2500_ about 2600, about 2800, about 3000, about 4000, about 5000, about 6000, about 7000, about 8000 mg mg/day. 1000 to 12000mg, about 2000 to 12000 mg, about 3000 to 12000 mg about 4000 to 12000 mg, about 5000 to 12000 mg, about 6000 to 12000 mg, about 1000 to 11000 mg, about 1000 to 10000 mg, about 1000 to 9000 mg, about 1000 to 8000 mg, or about 1000 to 7000 mg, which can be administered in single or multiple doses. In certain embodiments, the EPA or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000mg or any range derivable therein.
[0324] For oral administration, the pharmaceutical compositions provided herein can be formulated in the form of tablets or capsules containing from about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000mg of the compound of EPA or a pharmaceutically acceptable salt thereof for the symptomatic adjustment of the dosage to the patient to be treated.
[0325] In some embodiments, the EPA, or pharmaceutically acceptable salt thereof is administered in an amount of about or at most about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000 mg or any range derivable therein. In some embodiments, the EPA is administered in a range of about 1000 to 12000 mg/day, about 2000 to 12000 mg/day, about 3000 to 12000 mg/day about 4000 to 12000 mg/day, about 5000 to 12000 mg/day, about 6000 to 12000 mg/day, about 1000 to 11000 mg/day, about 1000 to 10000 mg/day, about 1000 to 9000 mg/day, about 1000 to 8000 mg/day, or about 1000 to 7000 mg/day. In some embodiments, the EPA or pharmaceutically acceptable salt thereof is derived from a natural source such that about or at most about 1 mg/day, about 10 mg/day, about 50 mg/day, about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 800 mg/day, about 900 mg/day, about 1000 mg/day, about 1100 mg/day, about 1200 mg/day, about 1300 mg/day, about 1400 mg/day, about 1500 mg/day, about 1600 mg/day, about 1700 mg/day, about 1800 mg/day, about 1900 mg/day, about 2000 mg/day, about 2100 mg/day, about 2200 mg/day, about 2300 mg/day, about 2400 mg/day, about 2500 mg/day, about 2600 mg/day, about 2700 mg/day, about 2800 mg/day, about 2900 mg/day, about 3000 mg/day, about 3100 mg/day, about 3200 mg/day, about 3300 mg/day, about 3400 mg/day, about 3500 mg/day, about 3600 mg/day, about 3700 mg/day, about 3800 mg/day, about 3900 mg/day, about 4000 mg/day, about 4100 mg/day, about 4200 mg/day, about 4300 mg/day, about 4400 mg/day, about 4500 mg/day, about 4600 mg/day, about 4700 mg/day, about 4800 mg/day, about 4900 mg/day, about 5000 mg/day about 5100 mg/day, about 5200 mg/day, about 5300 mg/day, about 5400 mg/day, about 5500 mg/day, about 5600 mg/day, about 5700 mg/day, about 5800 mg/day, about 5900 mg/day, about 6000 mg/day, about 6100 mg/day, about 6200 mg/day, about 6300 mg/day, about 6400 mg/day, about 6500 mg/day, about 6600 mg/day, about 6700 mg/day, about 6800 mg/day, about 6900 mg/day, about 7000 mg/day, about 7100 mg/day, about 7200 mg/day, about 7300 mg/day, about 7400 mg/day, about 7500 mg/day, about 7600 mg/day, about 7700 mg/day, about 7800 mg/day, about 7900 mg/day, about 8000 mg/day, about 8100 mg/day, about 8200 mg/day, about 8300 mg/day, about 8400 mg/day, about 8500 mg/day, about 8600 mg/day, about 8700 mg/day, about 8800 mg/day, about 8900 mg/day, about 9000 mg/day, about 9100 mg/day, about 9200 mg/day, about 9300 mg/day, about 9400 mg/day, about 9500 mg/day, about 9600 mg/day, about 9700 mg/day, about 9800 mg/day, about 9900 mg/day, or about 10000 mg/day, about 10100 mg/day, about 10200 mg/day, about 10300 mg/day, about 10400 mg/day, about 10500 mg/day, about 10600 mg/day, about 10700 mg/day, about 10800 mg/day, about 10900 mg/day, about 11000 mg/day about 11100 mg/day, about 11200 mg/day, about 11300 mg/day, about 11400 mg/day, about 11500 mg/day, about 11600 mg/day, about 11700 mg/day, about 11800 mg/day, about 11900 mg/day, or about 12000mg/day EPA or pharmaceutically acceptable salt thereof is administered.
103261 In some embodiments, the natural source comprises at least or about 1 mg/g, about 5 mg/g, about 10 mg/g, about 15 mg/g, about 20 mg/g, about 25 mg/g, about 30 mg/g, about 35 mg/g, about 40 mg/g, about 45 mg/g, about 50 mg/g, about 55 mg/g, about 60 mg/g, about 65 mg/g, about 70 mg/g, about 75 mg/g, or about 80 mg/g of EPA or a pharmaceutically acceptable salt thereof In some embodiments, the natural source comprises at least or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than 95% of a compound of EPA or pharmaceutically acceptable salt thereof.
103271 In certain embodiments, in the treatment, prevention, or amelioration of one or more symptoms of the disorders, diseases, or conditions described herein, an appropriate dosage level of the compound of DHA or a pharmaceutically acceptable salt thereof generally is ranging from about 1 to 12000 mg, from about 1000 to 12000mg, about 2000 to 12000 mg, about 3000 to 12000 mg about 4000 to 12000 mg, about 5000 to 12000 mg, about 6000 to 12000 mg, about 1000 to 11000 mg, about 1000 to 10000 mg, about 1000 to 9000 mg, about 1000 to 8000 mg, or about 1000 to 7000 mg, which can be administered in single or multiple doses. In certain embodiments, the DHA or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000mg or any range derivable therein.
103281 In certain embodiments, the DHA, or pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 275 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000, about 1200, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, about 2400, about 2500, about 2600, about 2800, about 3000, about 4000, about 5000, about 6000, about 7000, about 8000 mg mg/day. 1000 to 12000mg, about 2000 to 12000 mg, about 3000 to 12000 mg about 4000 to 12000 mg, about 5000 to 12000 mg, about 6000 to 12000 mg, about 1000 to 11000 mg, about 1000 to 10000 mg, about 1000 to 9000 mg, about 1000 to 8000 mg, or about 1000 to 7000 mg, which can be administered in single or multiple doses. In certain embodiments, the DHA or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000mg or any range derivable therein.
[0329] For oral administration, the pharmaceutical compositions provided herein can be formulated in the form of tablets or capsules containing from about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000mg of the compound of DHA or a pharmaceutically acceptable salt thereof for the symptomatic adjustment of the dosage to the patient to be treated.
103301 In some embodiments, the DHA, or pharmaceutically acceptable salt thereof is administered in an amount of about or at most about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about MOO mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000 mg or any range derivable therein. In some embodiments, the DHA is administered in a range of about 1000 to 12000 mg/day, about 2000 to 12000 mg/day, about 3000 to 12000 mg/day about 4000 to 12000 mg/day, about 5000 to 12000 mg/day, about 6000 to 12000 mg/day, about 1000 to 11000 mg/day, about 1000 to 10000 mg/day, about 1000 to 9000 mg/day, about 1000 to 8000 mg/day, or about 1000 to 7000 mg/day. In some embodiments, the DHA or pharmaceutically acceptable salt thereof is derived from a natural source such that about or at most about 1 mg/day, about 10 mg/day, about 50 mg/day, about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 800 mg/day, about 900 mg/day, about 1000 mg/day, about 1100 mg/day, about 1200 mg/day, about 1300 mg/day, about 1400 mg/day, about 1500 mg/day, about 1600 mg/day, about 1700 mg/day, about 1800 mg/day, about 1900 mg/day, about 2000 mg/day, about 2100 mg/day, about 2200 mg/day, about 2300 mg/day, about 2400 mg/day, about 2500 mg/day, about 2600 mg/day, about 2700 mg/day, about 2800 mg/day, about 2900 mg/day, about 3000 mg/day, about 3100 mg/day, about 3200 mg/day, about 3300 mg/day, about 3400 mg/day, about 3500 mg/day, about 3600 mg/day, about 3700 mg/day, about 3800 mg/day, about 3900 mg/day, about 4000 mg/day, about 4100 mg/day, about 4200 mg/day, about 4300 mg/day, about 4400 mg/day, about 4500 mg/day, about 4600 mg/day, about 4700 mg/day, about 4800 mg/day, about 4900 mg/day, about 5000 mg/day about 5100 mg/day, about 5200 mg/day, about 5300 mg/day, about 5400 mg/day, about 5500 mg/day, about 5600 mg/day, about 5700 mg/day, about 5800 mg/day, about 5900 mg/day, about 6000 mg/day, about 6100 mg/day, about 6200 mg/day, about 6300 mg/day, about 6400 mg/day, about 6500 mg/day, about 6600 mg/day, about 6700 mg/day, about 6800 mg/day, about 6900 mg/day, about 7000 mg/day, about 7100 mg/day, about 7200 mg/day, about 7300 mg/day, about 7400 mg/day, about 7500 mg/day, about 7600 mg/day, about 7700 mg/day, about 7800 mg/day, about 7900 mg/day, about 8000 mg/day, about 8100 mg/day, about 8200 mg/day, about 8300 mg/day, about 8400 mg/day, about 8500 mg/day, about 8600 mg/day, about 8700 mg/day, about 8800 mg/day, about 8900 mg/day, about 9000 mg/day, about 9100 mg/day, about 9200 mg/day, about 9300 mg/day, about 9400 mg/day, about 9500 mg/day, about 9600 mg/day, about 9700 mg/day, about 9800 mg/day, about 9900 mg/day, or about 10000 mg/day, about 10100 mg/day, about 10200 mg/day, about 10300 mg/day, about 10400 mg/day, about 10500 mg/day, about 10600 mg/day, about 10700 mg/day, about 10800 mg/day, about 10900 mg/day, about 11000 mg/day about 11100 mg/day, about 11200 mg/day, about 11300 mg/day, about 11400 mg/day, about 11500 mg/day, about 11600 mg/day, about 11700 mg/day, about 11800 mg/day, about 11900 mg/day, or about 12000mg/day DHA or pharmaceutically acceptable salt thereof is administered.
[0331] In some embodiments, the natural source comprises at least or about 1 mg/g, about 5 mg/g, about 10 mg/g, about 15 mg/g, about 20 mg/g, about 25 mg/g, about 30 mg/g, about 35 mg/g, about 40 mg/g, about 45 mg/g, about 50 mg/g, about 55 mg/g, about 60 mg/g, about 65 mg/g, about 70 mg/g, about 75 mg/g, or about 80 mg/g of DHA or a pharmaceutically acceptable salt thereof. In some embodiments, the natural source comprises at least or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than 95% of a compound of DHA or pharmaceutically acceptable salt thereof.
[0332] In some embodiments, a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and a fatty acid are administered at a ratio of about 1:1, about 1:5, about 1:10, about 1:15, about 1:20, about 1:25, about 1:30, about 1:35, about 1:40, about 1:45, about 1:50, about 1:55, about 1:60, about 1:65, about 1:70, about 1:75, about 1:80, about 1:85, about 1:90, about 1:95, about 1:100, about 1:150, about 1:200, about 1:250, about 1:300, about 1:350, about 1:400, about 1:450, about 1:500, about 1:550, about 1:600, about 1:650, about 1:700, about 1:750, about 1:800, about 1:850, about 1:900, about 1:950, or about 1:1000. In some embodiments, a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and an oleic acid are administered at a ratio of about 1:1, about 1:5, about 1:10, about 1:15, about 1:20, about 1:25, about 1:30, about 1:35, about 1:40, about 1:45, about 1:50, about 1:55, about 1:60, about 1:65, about 1:70, about 1:75, about 1:80, about 1:85, about 1:90, about 1:95, about 1:100, about 1:150, about 1:200, about 1:250, about 1:300, about 1:350, about 1:400, about 1:450, about 1:500, about 1:550, about 1:600, about 1:650, about 1:700, about 1:750, about 1:800, about 1:850, about 1:900, about 1:950, or about 1:1000. In some embodiments, a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and a EPA are administered at a ratio of about 1:1, about 1:5, about 1:10, about 1:15, about 1:20, about 1:25, about 1:30, about 1:35, about 1:40, about 1:45, about 1:50, about 1:55, about 1:60, about 1:65, about 1:70, about 1:75, about 1:80, about 1:85, about 1:90, about 1:95, or about 1:100. In some embodiments, a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and a DHA are administered at a ratio of about 1:1, about 1:5, about 1:10, about 1:15, about 1:20, about 1:25, about 1:30, about 1:35, about 1:40, about 1:45, about 1:50, about 1:55, about 1:60, about 1:65, about 1:70, about 1:75, about 1:80, about 1:85, about 1:90, about 1:95, about 1:100, about 1:150, about 1:200, about 1:250, about 1:300, about 1:350, about 1:400, about 1:450, about 1:500, about 1:550, about 1:600, about 1:650, about 1:700, about 1:750, about 1:800, about 1:850, about 1:900, about 1:950, or about 1:1000. In some embodiments, the pharmaceutical compositions provided herein can be formulated in the form of an injection or I. V. infusion containing a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated in the form of an injection or I.V.
infusion containing oleic acid or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated in the form of an injection or I.V. infusion containing DHA or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated in the form of an injection or I.V. infusion containing EPA or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated in the form of an injection or I.V.
infusion containing a compound of Formula (I); an oleic acid; EPA; DHA; a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof; or a combination thereof. The dose per day described herein may be given once per day or multiple times per day in the form of sub-doses given bid, t.i.d., q.i. d., or the like where the number of sub-doses equal the dose per day. The pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day. In some embodiments, the pharmaceutical compositions are administered once per day. In some embodiments, the pharmaceutical compositions are administered twice per day. In some embodiments, the pharmaceutical compositions are administered three times per day. In some embodiments, a loading dose, followed by maintenance doses, of the pharmaceutical compositions are administered.
[0333] In some embodiments, the pharmaceutical compositions provided herein are administered as a tablet. In some embodiments, the pharmaceutical compositions provided herein are administered as a capsule. In some embodiments, the pharmaceutical compositions provided herein are administered as an injection. In some embodiments, the pharmaceutical compositions provided herein are administered as an I.V. infusion.
[0334] In some embodiments, the pharmaceutical compositions provided herein are administered as an I.V. infusion over a period of about 15 minutes. In some embodiments, the pharmaceutical compositions provided herein are administered as an I.V. infusion over a period of about 30 minutes.
In some embodiments, the pharmaceutical compositions provided herein are administered as an I. V.
infusion over a period of about 45 minutes. In some embodiments, the pharmaceutical compositions provided herein are administered as an I.V. infusion over a period of about one hour. In some embodiments, the pharmaceutical compositions provided herein are administered as an I.V. infusion over a period of about two hours. In some embodiments, the pharmaceutical compositions provided herein are administered as an I.V. infusion over a period of about three hours or more.
[0335] In some embodiments, the pharmaceutical compositions provided herein are administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, or about 30 days.
[0336] In some embodiments, the pharmaceutical compositions provided herein are administered for administered daily, every other day, every other day 3 times a week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 3 days, every 4 days, every 5 days, every 6 days, weekly, bi-weekly, 3 times a week, 4 times a week, 5 times a week, 6 times a week, once a month, twice a month, 3 times a month, once every 2 months, once every 3 months, once every 4 months, once every months, or once every 6 months.
103371 In some instances, the method for the administration of multiple compounds (e.g., a compound of Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof) comprises administering compounds within 48 hours or less of each other. In some embodiments administration occurs within 24 hours, 12 hours, 6 hours, 3 hours, 1 hour, or 15 minutes. In some instances, the compounds are administered simultaneously. One example of simultaneous administration is the injection of one compound immediately before, after, or during the oral administration of the second compound, immediately referring to a time less than about 5 minutes.
[0338] In some embodiments of the pharmaceutical compositions described herein, a second dose is administered about 1 hour after the first dose, a second dose is administered about 2 hours after the first dose, a second dose is administered about 3 hours after the first dose, a second dose is administered about 4 hours after the first dose, a second dose is administered about 5 hours after the first dose_ a second dose is administered about 6 hours after the first dose, a second dose is administered about 7 hours after the first dose, a second dose is administered about 8 hours after the first dose, a second dose is administered about 9 hours after the first dose, a second dose is administered about 10 hours after the first dose, a second dose is administered about 11 hours after the first dose, or a second dose is administered about 12 hours after the first dose. In some embodiments of the pharmaceutical compositions described herein, the second dose is administered about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours after completion of administration of the first dose by I.V.
infusion. In some embodiments of the pharmaceutical compositions, the second dose is administered about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours after initiation of administration of the first dose by IV. infusion.
Subjects [0339] In some embodiments, the subject is immunocompromised. In some embodiments, the subject is an immunocompromised human subject. In some embodiments, the human subject is under the age of 1 year. In some embodiments, the human subject is an infant under 1 month old. In some embodiments, the human subject is over the age of 70 years.
[0340] In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human.
[0341] It is frequently beneficial to improve one of more physical properties of the treatment modalities disclosed herein and/or the manner in which they are administered.
Improvements of physical properties include, for example, methods of increasing water solubility, bi availability, serum half-life, and/or therapeutic half-life; and/or modulating biological activity. Modifications known in the art include pegylation, Fc-fusion and albumin fusion. Although generally associated with large molecule agents (e.g., polypeptides), such modifications have recently been evaluated with particular small molecules. By way of example, Chiang, M. et al. (J. Am. Chem.
Soc., 2014, 136(9):3370-73) describe a small molecule agonist of the adenosine 2a receptor conjugated to the immunoglobulin Fc domain. The small molecule-Fc conjugate retained potent Fc receptor and adenosine 2a receptor interactions and showed superior properties compared to the unconjugated small molecule. Covalent attachment of PEG molecules to small molecule therapeutics has also been described (Li, W. et al., Progress in Polymer Science, 2013 38:421-44).
[0342] The compounds of the present disclosure may be administered to a subject in an amount that is dependent upon, for example, the goal of administration (e.g., the degree of resolution desired); the age, weight, sex, and health and physical condition of the subject to which the formulation is being administered; the route of administration; and the nature of the disease, disorder, condition or symptom thereof. The dosing regimen may also take into consideration the existence, nature, and extent of any adverse effects associated with the agent(s) being administered.
Effective dosage amounts and dosage regimens can readily be determined from, for example, safety and dose-escalation trials, in vivo studies (e.g., animal models), and other methods known to the skilled artisan.
[0343] In general, dosing parameters dictate that the dosage amount be less than an amount that could be irreversibly toxic to the subject (the maximum tolerated dose (MTD)) and not less than an amount required to produce a measurable effect on the subject. Such amounts are determined by, for example, the pharmacokinetic and pharmacodynamic parameters associated with ADME, taking into consideration the route of administration and other factors.
[0344] An effective dose (ED) is the dose or amount of an agent that produces a therapeutic response or desired effect in some fraction of the subjects taking it. The -median effective dose- or ED50 of an agent is the dose or amount of an agent that produces a therapeutic response or desired effect in 50%
of the population to which it is administered. Although the ED50 is commonly used as a measure of reasonable expectance of an agent's effect, it is not necessarily the dose that a clinician might deem appropriate taking into consideration all relevant factors. Thus, in some situations the effective amount is more than the calculated ED50, in other situations the effective amount is less than the calculated ED50, and in still other situations the effective amount is the same as the calculated ED50.
[0345] In addition, an effective dose of the compounds of the present disclosure may be an amount that, when administered in one or more doses to a subject, produces a desired result relative to a healthy subject. For example, for a subject experiencing a particular disorder, an effective dose may be one that improves a diagnostic parameter, measure, marker and the like of that disorder by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, where 100% is defined as the diagnostic parameter, measure, marker and the like exhibited by a normal subject.
[0346] In embodiments, the dosage of the desired compound is contained in a -unit dosage form."
The phrase "unit dosage form" refers to physically discrete units, each unit including a predetermined amount of the compound (e.g., a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof), sufficient to produce the desired effect. It will be appreciated that the parameters of a unit dosage form will depend on the particular agent and the effect to be achieved.
NUMBERED EMBODIMENTS
[0347] Numbered embodiment 1 comprises a composition, comprising: (i) a compound of structural Formula (I):
R1)n2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
R' is independently hydrogen, halogen, ¨OR'-, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1-6 alkyl; and RIP' is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and (ii) a fatty acid, wherein a ratio of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and the fatty acid is in a range of about 1:5 to about 1:1000.
Numbered embodiment 2 comprises a composition of numbered embodiment 1, wherein the compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 0.1%(w/v) to about 50% (w/v). Numbered embodiment 3 comprises a composition of any one of numbered embodiments 1-2, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 10% (w/v). Numbered embodiment 4 comprises a composition of any one of numbered embodiments 1-3, wherein the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of less than about 2% (w/v). Numbered embodiment 5 comprises a composition of any one of numbered embodiments 1-4, wherein the fatty acid is a cannabinoid.
Numbered embodiment 6 comprises a composition of any one of numbered embodiments 1-5, wherein the fatty acid is a polyunsaturated fatly acid (PUFA). Numbered embodiment 7 comprises a composition of any one of numbered embodiments 1-6, wherein the PUFA is anandamide.
Numbered embodiment 8 comprises a composition of any one of numbered embodiments 1-7, wherein the PUFA is a cannabinoid. Numbered embodiment 9 comprises a composition of any one of numbered embodiments 1-8, wherein the PUFA is a n-3 PUFA. Numbered embodiment 10 comprises a composition of any one of numbered embodiments 1-9, wherein the PUFA is a n-6 PUFA. Numbered embodiment 11 comprises a composition of any one of numbered embodiments 1-10, wherein the fatty acid is an omega-3 fatty acid. Numbered embodiment 12 comprises a composition of any one of numbered embodiments 1-11, wherein the omega-3 fatty acid is DHA
(docosahexaenoic acid), EPA (eicosapentaenoic acid), LNA (linolenic acid), or combinations thereof.
Numbered embodiment 13 comprises a composition of any one of numbered embodiments 1-12, wherein the omega-3 fatty acid is DHA (docosahexaenoic acid), EPA
(eicosapentaenoic acid), LNA
(linolenic acid), or combinations thereof. Numbered embodiment 14 comprises a composition of any one of numbered embodiments 1-13, wherein the fatty acid is oleic acid or erucic acid. Numbered embodiment 15 comprises a composition of any one of numbered embodiments 1-14, wherein a ratio of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and the fatty acid is in a range of about 1:20 to about 1:100.
Numbered embodiment 16 comprises a composition of any one of numbered embodiments 1-15, wherein a ratio of the compound of Formula (1) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and the fatty acid is about 1:60. Numbered embodiment 17 comprises a composition of any one of numbered embodiments 1-16, wherein the composition is in a form for oral dosing or administration.
Numbered embodiment 18 comprises a composition of any one of numbered embodiments 1-17, wherein the compound of structural Formula (I) has structural Formula (I-A):
R1=1 n1 0 n3 (I-A), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
R" is hydrogen, halogen, ¨ORIJA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
10.2 is hydrogen, halogen, ¨0RI.2A, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and R1.1A and R1.2A are independently hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONHI, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
Numbered embodiment 19 comprises a composition of any one of numbered embodiments 1-18, wherein:
R" is CH3; and R1.2 is OH.
Numbered embodiment 20 comprises a composition of any one of numbered embodiments 1-19, wherein X is 0. Numbered embodiment 21 comprises a composition of any one of numbered embodiments 1-20, wherein X is NH. Numbered embodiment 22 comprises a composition of any one of numbered embodiments 1-21, wherein is a double bond. Numbered embodiment 23 a comprises a composition of any one of numbered embodiments 1-22, wherein = is a single bond.
Numbered embodiment 24 comprises a composition of any one of numbered embodiments 1-23, wherein n1 is 2. Numbered embodiment 25 comprises a composition of any one of numbered embodiments 1-24, wherein n1 is 1. Numbered embodiment 26 comprises a composition of any one of numbered embodiments 1-25, wherein n1 is 0. Numbered embodiment 27 comprises a composition of any one of numbered embodiments 1-26, wherein R2 is unsubstituted alkyl.
Numbered embodiment 28 comprises a composition of any one of numbered embodiments 1-27, wherein R2 is ¨CH(CH3)2 or ¨CH3. Numbered embodiment 29 comprises a composition of any one of numbered embodiments 1-28, wherein the compound is at least one of:
HO HO Si HO HO
HO HO
HO HO
HO
HO is , or HO
0 =
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
Numbered embodiment 30 comprises a composition of any one of numbered embodiments 1-29, HO
wherein the compound is: 0 or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof Numbered embodiment 31 comprises a composition of any one of numbered embodiments 1-30, wherein the compound of structural Formula (I) is capsaicin. Numbered embodiment 32 comprises a composition of any one of numbered embodiments 1-31, wherein the compound of structural Formula (1) is dihydrocapsaicin. Numbered embodiment 33 comprises a method of treating or preventing a capsaicin-responsive disease or disorder, comprising administering to a subject in need thereof the composition of any one of numbered embodiments 1-32. Numbered embodiment 34 comprises a method of any one of numbered embodiments 1-33, wherein the disease or disorder is a cell proliferative disease, obesity, diabetes, a bacterial infection, a cardiovascular disease, a neurodegenerative disease or disorder, an inflammatory disease or disorder, a comorbidity, an autoimmune disease, hypercholesterolemia or a mood disorder. Numbered embodiment 35 comprises a method of any one of numbered embodiments 1-34, wherein the mood disorder is depression. Numbered embodiment 36 comprises a method of any one of numbered embodiments 1-35, wherein the inflammatory disease or disorder is rheumatoid arthritis.
Numbered embodiment 37 comprises a method of any one of numbered embodiments 1-36, wherein the cell proliferative disease is a cancer. Numbered embodiment 38 comprises a method of any one of numbered embodiments 1-36, wherein the disorder is diabetes or obesity. Numbered embodiment 39 comprises a method of any one of numbered embodiments 1-38, wherein the comorbidity is chronic kidney disease, stroke, congestive heart failure, dementia, schizophrenia, hepatitis, autism spectrum disorder, HIV, or a combination thereof. Numbered embodiment 40 comprises a method of any one of numbered embodiments 1-39, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally.
Numbered embodiment 41 comprises a method of any one of numbered embodiments 1-40, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally via a suspension or solution. Numbered embodiment 42 comprises a method of any one of numbered embodiments 1-41, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally via a solid dosage form. Numbered embodiment 43 comprises a method of any one of numbered embodiments 1-42, wherein the form is a tablet or capsule. Numbered embodiment 44 comprises a method of any one of numbered embodiments 1-43, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by inhalation, nebulization, or nasal delivery. Numbered embodiment 45 comprises a method of any one of numbered embodiments 1-44, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by inhalation via a vaporizer. Numbered embodiment 46 comprises a method of any one of numbered embodiments 1-45, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered parenterally. Numbered embodiment 47 comprises a method of any one of numbered embodiments 1-46, the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered via parenteral injection, infusion, or implantation. Numbered embodiment 48 comprises a method of any one of numbered embodiments 1-47, wherein the parenteral injection is intravenous, intramuscular, subcutaneous, or intradermal. Numbered embodiment 49 comprises a method of any one of numbered embodiments 1-48, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered via a suppository. Numbered embodiment 50 comprises a method of any one of numbered embodiments 1-49, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered cutaneous or transdermal delivery. Numbered embodiment 51 comprises a method of any one of numbered embodiments 1-50, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by sublingual or buccal delivery. Numbered embodiment 52 comprises a method of any one of numbered embodiments 1-51, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the fatty acid are administered simultaneously, approximately simultaneously, or sequentially, in any order. Numbered embodiment 53 comprises a method of any one of numbered embodiments 1-52, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the fatty acid are administered simultaneously or approximately simultaneously. Numbered embodiment 54 comprises a method of any one of numbered embodiments 1-53, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the fatty acid are administered sequentially. Numbered embodiment 55 comprises a method of any one of numbered embodiments 1-54, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is released before the fatty acid.
Numbered embodiment 56 comprises a method of any one of numbered embodiments 1-55, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is released after the fatty acid.
EXAMPLES
Example 1: Effects of fatty acids on tolerance to capsaicinoids (capsaicin or dihydrocapsaicin) in C57BL/63Itj mice [0348] The ability of oleic acid (OA) and eicosapentanenoic acid (EPA) to prevent capsacinoid-induced intolerance was assessed in 42-week old male C57BL/6.11kj mice. Mice were randomized to the following five groups (n=12/group): (1) Vehicle control (615 mg/Kg body weight cottonseed oil);
(2) Capsaicin + OA (10 mg/kg capsaicin + 615 mg/kg oleic acid); (3) Capsaicin + EPA (10 mg/kg capsaicin + 615 mg/kg EPA); (4) Dihy drocapsaicin + OA (2 mg/kg dihydrocapsaicin + 615 mg/kg oleic acid); and (5) Dihydrocapsaicin + EPA (2 mg/kg dihydrocapsaicin + 615 mg/kg EPA). The human equivalent doses of capsaicin and dihydrocapsaicin were calculated via allometric scaling to be 114 mg/day and 26 mg/day, respectively. Animals were administered the formulations via oral gavage in a volume of 5 mL/kg) twice daily for 42 days. Food intake was measured daily for the first 14-days, and the following clinical signs of distress or discomfort were assessed daily throughout the study: Unusual aggression, change in appetite or feeding behavior, change in activity/restlessness, decrease in grooming, excessive licking and scratching/self-mutilation, abnormal stance/hunched posture, rapid respiration. There was no significant among groups for food and/or water intake (Fig.
1), indicating that the inclusion of OA or EPA suppressed the commonly observed alterations in appetite with capsaicinoid administration.
[0349] The administration of all substances was well-tolerated and equally tolerated among groups, with no clinical signs of distress evident in any animal from the first dose (dose 1, day 1) to the final dose (dose 84, day 42).
Example 2: Effects of Capsaicinoid-EPA Combinations on Hepatic Outcomes in a Mouse Model of Diet-Induced Obesity and Non-Alcoholic Steatosis (NASH) [0350] Five-week old male C57BL/6Rj mice were fed a high fat (40%) containing 20% fructose and 2% cholesterol for 37 weeks to induce modest obesity and NASH. They were then randomized to the following three groups (n=12/group) using magnetic resonance imaging (MRI) of body fat to ensure equivalent adiposity across groups: (1) Vehicle control (615 mg/Kg body weight cottonseed oil); (2) Capsaicin (Cap) + EPA (10 mg/kg cap + 615 mg/kg EPA); and (3) DHC + EPA (2 mg/kg DHC + 615 mg/kg EPA). Animals were administered the formulations via oral gavage in a volume of 5 mL/kg) twice daily for 42 days. At the conclusion of the study animals were fasted for four hours and then terminated and the livers removed, weighed, and biopsied for steatosis via quantitative hematoxylin and eosin (H&E) staining, inflammation via immunohistochemistry (IHC) for Galectin-3 (Gal-3), stellate cell activation via IHC for a-smooth muscle actin (a-SMA) and fibrosis via IHC for collagen (Collal). Treatment with either Capsaicin-EPA or DHC-EPA resulted in a significant decrease in hepatic steatosis (Fig. 2), and in stellate cell activation (a-SMA; Fig. 3).
There was a trend towards decreasing fibrosis (Collal), but Collal changes were not statistically significant (Fig. 4). However, changes in fibrosis generally take longer to manifest (>12 weeks, vs. the 6-week duration of this study).
103511 There were no significant effects or trends evident for Gal-3. These data demonstrate that capsaicinoid-EPA combinations significantly reverse diet-induced steatosis and stellate cell activation in this mouse model of NASH. The effects on stellate cell activation indicate an anti-fibrotic effect that will manifest as reduced collagen (Col lad) over longer periods of treatment.
Example 3. Effects of Capsaicinoid-OA Combinations on Body Weight and Adiposity in a Mouse Model of Diet-Induced Obesity [0352] Five-week old male C57BL/6Rj mice were fed a high fat (40%) containing 20% fructose and 2% cholesterol for 37 weeks to induce modest obesity. They were then randomized to the following three groups (n=12/group) using magnetic resonance imaging (MRI) of body fat to ensure equivalent adiposity across groups: (1) Vehicle control (615 mg/Kg body weight cottonseed oil); (2) Capsaicin (Cap) + OA (10 mg/kg cap + 615 mg/kg OA); and (3) DHC + OA (2 mg/kg DHC + 615 mg/kg OA).
Animals were administered the formulations via oral gavage in a volume of 5 mL/kg) twice daily for 42 days. Body weight was measured daily, and adiposity (body fat mass) was measured via MRI at study conclusion. DHC+0A reduced body weight compared to vehicle control (Fig.
5). This effect was evident by day 5 and persisted throughout the 42-day study. Cap-OA exerted no effect on weight. This was reflected in a significant decrease in body fat in the DHC+0A
group and a corresponding decrease in body fat as a percentage of body weight at the conclusion of the study (Fig. 6).
[0353] These data indicate that DHC-0A, but not Cap-OA, exerts an anti-obesity effect in this animal model of obesity.
Example 4. Effects of capsaicinoid-fatty acid combinations on glucose tolerance and insulin sensitivity in diabetic mice.
[0354] Eighty-four male db/db mice (BKS. CG-Dock7m+/+LeprdbJ) are randomized at 8 weeks of age to produce seven equivalent groups (n=12/group) with respect to 4-hour fasting glucose and body weight. Treatment groups are as follow: Control (untreated); Capsaicin (5 mg/kg)+0A (615 mg/kg);
DHC (1 mg/kg)+0A (615 mg/kg); capsaicin (10 mg/kg)+0A (615 mg/kg); DHC (10 mg/kg)+0A
(615 mg/kg); capsaicin (5 mg/kg); DHC (1 mg/kg). Animals are administered the formulations via oral gavage in a volume of 5 mL/kg) twice daily for 28 days. Blood glucose is measured following a four hour fast on days 0,7, 14, 21 and 28. On day 28, an oral glucose tolerance test (OG I 1) is performed following a four-hour fast. Glucose (1.2 g/kg) is dosed at t=10 minutes, and glucose and insulin are measured at t=-60 minutes, 0, 15, 30, 60, 120, 180 and 240 minutes.
[0355] Fasting glucose is 300 mg/dL in the control group and is dose-responsively decreased to 200 mg/dL by both the capsaicin+0A and DHC+0A treatments. This is effect is evident within 7 days of treatment and is maintained throughout the rest of the study, and there is no significant difference between the capsaicin+0A and DHC+0A combinations Area under the glucose curve for the OGTT
is dose-responsively decreased by 50%, and area under the insulin response curve during OGTT is dose-responsively decreased by 60% by the capsaicinoid-fatty acid combinations, with no significant difference between the capsaicin+0A and DHC+0A combinations. Capsaicin and DHC
administered in the absence of OA are poorly tolerated and the animals do not adapt during the first 72 hours (6 doses); consequently, these two groups are discontinued for animal welfare reasons.
Example 5. Fatty acid modulators reduce capsacinoid-induced TRPV1 signaling in vitro.
103561 The aim of this study was to evaluate the effects of oleic acid on antagaonizing capsaicinoid-induced TRPV1 primary signaling in Human dorsal root ganglia (DRG) neurons in culture. Human DRG neurons were studied in a perfusion system using the calcium dye Fluo-8.
Detection of intracellular calcium transients was accomplished by measuring the changes in the fluorescence intensity of the Fluo-8 calcium indicator upon excitation at 480 nm and recording of the emitted signal at 520 nm using a pcoEDGE sCMOS camera mounted on an inverted microscope (Olympus IX71). The following protocol was utilized to study the effects of the fatty acids on capsaicin and DHC-stimulated calcium currents.
Table 1: Protocol for study Acquisition Application Sequence Rate 1 image every Vehicle (Baseline) 30sec recorded 15sec 1 image every Vehicle (control) or OA (5min) 4.5min recorded 15sec Agonist First Application Sequence 1 image every Baseline with Vehicle or OA 30sec recorded 5sec Agonist (capsaicin or DHC) 1 image every 30sec recorded 1/2 5sec 1 image every Washout 4min recorded 5sec 1 image every Washout 10min recorded 15sec [0357] Treatment with capsaicin alone resulted in 74% of the treated neurons responding, and this figure was reduced to 51% by oleic acid administration. Treatment with DHC
alone resulted in 59%
of the neurons responding, and this figure was reduced to 38% by oleic acid administration, with a corresponding reduction in maximal calcium (AF/F0) signal from 4.57 to 2.81.
103581 Calcium imaging over time is shown in Figs. 7A-7D. These data indicate significant attenuation of TRPV1 signaling by oleic acid.
Example 6: The effect of capsaicin and a TrpV1 inhibitor on Resting Metabolic Weight.
103591 Detailed Description: This study is a double-blind, placebo-controlled, single center, randomized, parallel arm clinical trial to test the impact of capsaicin and a TrpV1 inhibitor as described below ingested for 4 weeks on resting metabolic rate and fat oxidation measured by indirect calorimetry.
Primary Outcome The consumption of capsaicin and a TrpV1 inhibitor will significantly increase resting Measures energy expenditure and fat oxidation [ Time Frame: 4 weeks ].
Descriptive Information A 4 week intake of drug combination to find a natural substance that may modify Brief Title energy balance and may enhance health in combination with lifestyle changes with possible decrease in body weight.
Effect of 4-week Capsaicin and a TrpV1 Inhibitor Ingestion on Resting Metabolic Official Title Rate: A Double-blind Randomized Parallel Arm Study A 4 week intake of drug to find a natural substance that may modify energy balance Brief Summary and may enhance health in combination with lifestyle changes with possible decrease in body weight Study Type Interventional Study Phase Phase 2 Allocation: Randomized Intervention Model: Parallel Assignment Study Design Masking: Double (Participant, Investigator) Primary Purpose: Prevention Condition Obesity, Weight = Other: Capsaicin in combination a TrpV1 inhibitor (EPA or oleic acid) Intervention = Capsules will contain 0.1%, 1%, or 10% (w/v) capsaicin and a TrpV1 inhibitor in a range of about 1:5 to about 1:1000.
= Placebo Comparator: Sugar pill (Placebo 0 mg/d) 0 mg/d sugar pill Study Arms Intervention: Other: Capsaicin and TrpV1 inhibitor combination = Active Comparator: Capsaicin and TrpV1 combination (EPA) Drug 0.1% (w/v) including Placebo Intervention: Other: Capsaicin and TrpV1 inhibitor combination = Active Comparator: 1% (w/v) capsaicin and a TrpV1 inhibitor (EPA) Drug 1% (w/v) including Placebo Intervention: Other: capsaicin and a TrpV1 inhibitor combination = Active Comparator: Capsaicin and TrpV1 combination (EPA) Drug 10% (w/v) including Placebo Intervention: Other: Capsaicin and TrpV1 inhibitor combination = Active Comparator: Capsaicin and TrpV1 combination (oleic acid) Drug 0.1% (w/v) including Placebo Intervention: Other: Capsaicin and TrpV1 inhibitor combination = Active Comparator: 1% (w/v) capsaicin and a TrpV1 inhibitor (oleic acid) Drug 1% (w/v) including Placebo Intervention: Other: capsaicin and a TrpV1 inhibitor combination = Active Comparator: Capsaicin and TrpV1 combination (oleic acid) Drug 10% (w/v) including Placebo Intervention: Other: Capsaicin and TrpV1 inhibitor combination Recruitment Information Inclusion Criteria:
= Men between 20-60 years old = Healthy as assessed by medical history and standard medical exam = Weight-stable = Body mass index of 25 to 34.9 kg/m2 = Non-smoker = Sedentary lifestyle: not being physically active greater than 3 days/week for 20 min each time for the previous 6 months, and not participating in regular resistance exercise.
Eligibility Exclusion Criteria:
Criteria = Subjects enrolled in a diet to increase or decrease body weight = Special diet or food aversions to common foods = Has allergy to chili pepper = Eating chili peppers on a daily basis = Usually consuming more than 2 cups of tea or coffee/day = Usually consuming more than 4 cans of caffeinated soft drinks a day = Usually consuming more than 3 standard alcohol drinks/day = Regular use of medications (weight loss drugs, drugs affecting energy metabolism, drugs for depression) ...................... ......................... .............................
............ ............ ................ ............ ............
............................. ............ ............
............................. ............ ........
= Usual intake of illicit substances = Claustrophobia = Participating or having participated in another clinical trial during the last 4 weeks prior to the beginning of this study Sex/Gender Sexes Eligible for Study: All Ages 20 years to 60 years (Adult, Older Adult) Accepts Healthy Yes Volunteers Outcome Respiratory calorimetry on days 0, 7 and 28 of the intervention to assess energy expenditure and respiratory quotient/substrate oxidation under fasting conditions Measurement (resting energy expenditure) and one-hour following a standardized meal.
[0360] Although the disclosure has been described with reference to the above example, it will be understood that modifications and variations are encompassed within the spirit and scope of the disclosure. Accordingly, the disclosure is limited only by the following claims.
tumor virus, Ross River virus, Rotavirus, rougeole virus, Rous sarcoma virus, rubella virus, rubeola virus, Rubivirus, Russian autumn encephalitis virus, SA 11 simian virus, SA2 virus, S abi a virus, Sagiyama virus, Saimirine herpesvirus 1, salivary gland virus, sandfly fever virus group, Sandjimba virus, SARS virus, SDAV
(sialodacryoadenitis virus), sealpox virus, Semliki Forest Virus, Seoul virus.
sheeppox virus, Shope fibroma virus, Shope papilloma virus, simian foamy virus, simian hepatitis A
virus, simian human immunodeficiency virus, simian immunodeficiency virus, simian parainfluenza virus, simian T cell lymphotrophic virus, simian virus, simian virus 40, Simplexvirus, Sin Nombre virus, Sindbis virus, smallpox virus, South American hemorrhagic fever viruses, sparrowpox virus, Spumavirus, squirrel fibroma virus, squirrel monkey retrovirus, SSV 1 virus group, STLV (simian T
lymphotropic virus) type I, STLV (simian T lymphotropic virus) type II, STLV (simian T
lymphotropic virus) type III, stomatitis papulosa virus, submaxillary virus, suid alphaherpesvirus 1, suid herpesvirus 2, Suipoxvirus, swamp fever virus, swinepox virus, Swiss mouse leukemia virus, TAC virus, Tacaribe complex virus, Tacaribe virus, Tanapox virus, Taterapox virus, Tench reovirus, Theiler's encephalomyelitis virus, Theiler's virus, Thogoto virus, Thottapalayam virus, Tick borne encephalitis virus, Tioman virus, Togavirus, Torovirus, tumor virus, Tupaia virus, turkey rhinotracheitis virus, turkeypox virus, type C retroviruses, type D oncovirus, type D retrovirus group, ulcerative disease rhabdovirus, Una virus, Uukuniemi virus group, vaccinia virus, vacuolating virus, varicella zoster virus, Varicellovirus, Varicola virus, variola major virus, variola virus, Vasin Gishu disease virus, VEE virus, Venezuelan equine encephalitis virus, Venezuelan equine encephalomyelitis virus, Venezuelan hemorrhagic fever virus, vesicular stomatitis virus, Vesiculovirus, Vilyuisk virus, viper retrovirus, viral haemorrhagic septicemia virus, Visna Maedi virus, Visna virus, volepox virus, VSV
(vesicular stomatitis virus), Wallal virus, Warrego virus, wart virus, WEE
virus, West Nile virus, western equine encephalitis virus, western equine encephalomyelitis virus, Whataroa virus, Winter Vomiting Virus, woodchuck hepatitis B virus, woolly monkey sarcoma virus, wound tumor virus, WRSV virus, Yaba monkey tumor virus, Yaba virus, Yatapoxvirus, yellow fever virus, or the Yug Bogdanovac virus. In some embodiments, the infectious disease is caused by the coronavirus.
[0052] The disease may be a cancer. In some further instances, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophagus, and liver cancer, including hepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Cell lymphomas), Hodgkin's lymphoma, leukemia (including MDS, AML, ALL, ATLL and CML), or multiple myeloma. As used herein, the term "cancer"
refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g. humans), including leukemia, carcinomas and sarcomas. Exemplary cancers that may be treated with a compound or method provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer, lung cancer, and cancer of the head. Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head & neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, Medulloblastoma, colorectal cancer, pancreatic cancer. Additional examples include, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.
[0053] The term "leukemia" refers broadly to progressive, malignant diseases of the blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved;
myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocy tic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.
[0054] The term "sarcoma generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma. liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B
cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.
[0055] The term "melanoma" is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.
[0056] The term "carcinoma" refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with a compound or method provided herein include, for example, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, I enticular carcinoma, carcinoma lenti cul are, lipomatous carcinoma, lymphoepitheli al carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.
[0057] As used herein, the term "autoimmune disease" refers to a disease or condition in which a subject's immune system has an aberrant immune response against a substance that does not normally elicit an immune response in a healthy subject. Examples of autoimmune diseases that may be treated with a compound, pharmaceutical composition, or method described herein include Acute Disseminated Encephalomyelitis (ADEM), Acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome (AP S), Autoimmune angi oedema, Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmune hepatitis, Autoimmune hyperlipidemia, Autoimmune immunodeficiency, Autoimmune inner ear disease (A1ED), Autoimmune myocarditis_ Autoimmune oophoritis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic purpura (ATP), Autoimmune thyroid disease, Autoimmune urticaria, Axonal or neuronal neuropathies, Balo disease, Behcet's disease, Bullous pemphigoid, Cardiomyopathy, Castleman disease, Celiac disease, Chagas disease, Chronic fatigue syndrome, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal ostomyelitis (CRM0), Churg-Strauss syndrome, Cicatricial pemphigoid/benign mucosal pemphigoid, Crohn's disease, Cogans syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST disease, Essential mixed cryoglobulinemia, Demyelinating neuropathies, Dermatitis herpetiformis, Dermatomyositis, Devic's disease (neuromyelitis optica), Discoid lupus, Dressler's syndrome, Endometriosis, Eosinophilic esophagitis, Eosinophilic fasciitis, Erythema nodosum, Experimental allergic encephalomyelitis, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, Goodpasture's syndrome, Granulomatosis with Polyangiitis (GPA) (formerly called Wegener's Granulomatosis), Graves' disease, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura, Herpes gestationis, Hypogammaglobulinemi a, Idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, Immunoregulatory lipoproteins, Inclusion body myositis, Interstitial cystitis, Juvenile arthritis, Juvenile diabetes (Type 1 diabetes). Juvenile mvositis, Kawasaki syndrome, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus (SLE), Lyme disease, chronic, Meniere's disease, Microscopic polyangiitis, Mixed connective tissue disease (MC'TD), Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica (Devic's), Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus), Paraneoplastic cerebellar degeneration, Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Parsonnage-Turner syndrome, Pars planitis (peripheral uveitis), Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia, POEMS
syndrome, Polyarteritis nodosa, Type I, II, & III autoimmune polyglandular syndromes, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Progesterone dermatitis, Primary biliary cirrhosis, Primary sclerosing cholangitis, Psoriasis, Psoriatic arthritis, Idiopathic pulmonary fibrosis, Pvoderma gangrenosum, Pure red cell aplasia, Raynauds phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Reiter's syndrome, Relapsing poly chondritis, Restless legs syndrome, Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren's syndrome, Sperm &
testicular autoimmunity, Stiff person syndrome, Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia, Takayasu's arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (HP), Tolosa-Hunt syndrome, Transverse myelitis_ Type 1 diabetes, Ulcerative colitis, Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vesiculobullous dermatosis, Vitiligo, or Wegener's granulomatosis (i.e., Granulomatosis with Polyangiitis (GPA). In some embodiments, the autoimmune disease is not asthma.
[0058] As used herein, the term "inflammatory disease" refers to a disease or condition characterized by aberrant inflammation (e.g. an increased level of inflammation compared to a control such as a healthy person not suffering from a disease). Examples of inflammatory diseases include traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison's disease, Vitiligo,asthma, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystiti s, ath ero scl erosi s, and atopi c dermatitis.
[0059] The terms "treating" or "treatment" refer to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. The term "treating" and conjugations thereof, may include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing.
[0060] "Treating- or "treatment- as used herein (and as well-understood in the art) also broadly includes any approach for obtaining beneficial or desired results in a subject's condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease's transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable. In other words, "treatment" as used herein includes any cure, amelioration, or prevention of a disease. Treatment may prevent the disease from occurring;
inhibit the disease's spread; relieve the disease's symptoms (e.g., ocular pain, seeing halos around lights, red eye, very high intraocular pressure), fully or partially remove the disease's underlying cause, shorten a disease's duration, or do a combination of these things.
[0061] "Treating" and "treatment" as used herein include prophylactic treatment. Treatment methods include administering to a subject a therapeutically effective amount of a compound described herein.
The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of the compound, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compositions are administered to the subject in an amount and duration sufficient to treat the patient.
[0062] The terms "prevent," "preventing," and "prevention" refer to a decrease in the occurrence of disease symptoms in a patient. The preventing or prevention may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur absent treatment. In embodiments, prevent refers to slowing the progression of the disease, disorder or condition or inhibiting progression thereof to a harmful or otherwise undesired state.
[0063] "Patient" or "subject in need thereof" refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals including, but not limited to, fish and birds.F"effec In some embodiments, a patient is human.
[0064] Treatment, as referred to herein, also refers to the systemic delivery of the compounds disclosed herein to any type of plant, including trees, shrubs, flowering plants, foliage plants, house plants, groundcover and grass, and agronomic plants (including crops of agronomic plants).
[0065] An "effective amount- is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). An example of an -effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a -therapeutically effective amount." A "reduction- of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A
"prophylactically effective amount- of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An "activity decreasing amount," as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A "function disrupting amount," as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and irechnology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). The therapeutically effective amount can be ascertained by measuring relevant physiological effects, and it can be adjusted in connection with the dosing regimen and diagnostic analysis of the subject's condition, and the like. By way of example, measurement of the serum level of a compound of Formula (1) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof (or, e.g., a metabolite thereof) at a particular time post-administration may be indicative of whether a therapeutically effective amount has been administered.
[0066] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.
100671 As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
Adjusting the dose to achieve maximal therapeutic window efficacy or toxicity in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
[0068] The term -therapeutically effective amount," as used herein, refers to that amount of the therapeutic agent sufficient to ameliorate the disorder, as described above.
For example, for the given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy can also be expressed as --fold" increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control.
[0069] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present disclosure should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.
Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
[0070] As used herein, the term -administering- means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By "co-administer- it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g., chemotherapeutic agent). The compound of the disclosure can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent).
Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). The compositions of the present disclosure can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols_ Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. The compositions of the present disclosure may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates.
These components are discussed in greater detail in U.S. Pat. Nos. 4.911,920; 5,403,841; 5,212,162;
and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.
The compositions of the present disclosure can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, I
Btomater Sci. Polym. Ed.
7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res.
12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, I Pharm.
Pharmacol. 49:669-674, 1997). In another embodiment, the formulations of the compositions of the present disclosure can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing receptor ligands attached to the liposome, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries receptor ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present disclosure into the target cells in vivo. (See, e.g., Al-Muhammed, I
Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. I Hosp.
Pharm. 46:1576-1587, 1989). The compositions of the present disclosure can also be delivered as nanoparticles.
[0071] By "co-administer" it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the disclosure can be administered alone or can be coadministered to the patient.
Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). The compositions of the present disclosure can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
[0072] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.
[0073] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
[0074] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present disclosure should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.
[0075] Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
[0076] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.
[0077] The compounds described herein can be used for treating an infectious disease. In some embodiments, the compounds described herein are used as an anti-coagulant. The compounds described herein can be used in combination with one another, with other active agents known to be useful in treating cancer (e.g., colon cancer), cardiovascular disease, metabolic disease, immune or inflammatory disease or disorder, or an infectious disease or disorder.
[0078] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 2 days, 4 days, 1 week or 1 month of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and/or adjunctive agents may be linked or conjugated to one another. In some embodiments, the compounds described herein may be combined with treatments for cancer or infections (e.g., fungal infections, bacterial infections, viral infections, etc.) [0079] A "cell" as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaryotic cells.
Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.
[0080] "Control- or "control experiment- is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples).
[0081] The phrase -in a sufficient amount to effect a change" means that there is a detectable difference between a level of an indicator measured before (e.g., a baseline level) and after administration of a particular therapy. Indicators include any objective parameter (e.g., serum concentration) or subjective parameter (e.g., a subject's feeling of well-being).
[0082] -Substantially pure- indicates that a component makes up greater than about 50% of the total content of the composition, and typically greater than about 60% of the total polypeptide content.
More typically, "substantially pure" refers to compositions in which at least 75%, at least 85%, at least 90% or more of the total composition is the component of interest. In some cases, the polypeptide will make up greater than about 90%, or greater than about 95% of the total content of the composition (percentage in a weight per weight basis).
[0083] "Capsaicin" as used herein is also referred to as (6E)-N4(4-Hydroxy-3-methoxyphenyOmethy11-8-methylnon-6-enamide, (E)-N-(4-Hydroxy-3-methoxybenzy1)-methylnon-6-enamide, 8-Methyl-N-vanillyl-trans-6-nonenamide, trans-8-Methyl-N-vanillylnon-6-enamide, (E)-Capsaicin, Capsicine, Capsicin, and/or CPS and has the chemical structure:
1-10leo [0084] In some embodiments, the compound of structural Formula (I), is capsaicin or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
Compositions [0085] In an aspect, provided herein is a composition, comprising:
(i) a compound of structural Formula (I):
(R1)2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, -0R1A, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1-6 alkyl; and R1A is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
(ii) at least one additional therapeutic agent selected from:
a fatty acid amide hydrolase (FAAH) receptor inhibitor, and a specialized pro-resolving mediator (SPM), or a combination thereof; and (iii) at least one excipient.
[0086] In an aspect, provided herein is a composition, consisting essentially of:
(i) a compound of structural Formula (I):
(R1)2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨ORIA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1-6 alkyl; and RIA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
(ii) a transient receptor potential cation channel subfamily V member 1 (TrpV1) modulator; and (iii) at least one excipient.
[0087] In an aspect, provided herein is a composition, consisting essentially of:
(i) capsaicin, or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof;
(ii) a transient receptor potential cation channel subfamily V member 1 (TrpV1) modulator; and (iii) at least one excipient [0088] In an aspect, provided herein is a composition, consisting essentially of:
(i) capsaicin, or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof;
(ii) oleic acid; and (iii) at least one excipient.
100891 In an aspect, provided herein is a composition, comprising:
(i) a compound of structural Formula (I):
(R1)1-12 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨ORIA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1-6 alkyl; and RIA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
(ii) a transient receptor potential cation channel subfamily V member 1 (TrpV1) modulator; and (iii) at least one excipient, wherein when the compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is capsaicin, then the capsaicin is present in the composition in an amount in a range of 0. 1%(w/v) to about 50%
(w/v).
[0090] In an aspect, provided herein is a composition, comprising:
(i) a compound of structural Formula (I):
(R1)2 = X - - R2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨ORIA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1_6 alkyl; and RIA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONI-12, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and (ii) at least one additional therapeutic agent selected from:
a fatty acid amide hydrolase (FAAH) receptor inhibitor, and a specialized pro-resolving mediator (SPM), or a combination thereof.
[0091] In an aspect, provided herein is a composition, consisting essentially of:
(i) a compound of structural Formula (I):
(R1)112 410 X '.5 R2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨ORIA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1-6 alkyl; and RIA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and (ii) a transient receptor potential cation channel subfamily V member 1 (TrpV1) modulator.
100921 In an aspect, provided herein is a composition, consisting essentially of:
(i) capsai ci n, or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof; and (ii) a transient receptor potential cation channel subfamily V member 1 (TrpV1) modulator.
100931 In an aspect, provided herein is a composition, consisting essentially of:
(i) capsaicin, or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof; and (ii) oleic acid.
[0094] In an aspect, provided herein is a composition, comprising:
(i) a compound of structural Formula (I):
(R1)2 ni 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨010A, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R' is hydrogen or substituted or unsubstituted C 1 -6 alkyl; and RIA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and (ii) a transient receptor potential cation channel subfamily V member 1 (TrpV1) modulator;
wherein when the compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is capsaicin, then the capsaicin is present in the composition in an amount in a range of 0.1%(w/v) to about 50%
(w/v).
[0095] In some embodiments, when the compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is capsaicin, gingerols, piperines, or shogaols, then the capsaicin, gingerols, piperines, or shogaols are present in the composition in an amount 0.1%(w/v) to about 50% (w/v). In some embodiments, when the compound of structural Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is capsaicin, guai acol , eugenol, Zingerone, ci yam i de, nonivamide, nuvanil, olvanil, NE-19550, NE-21610, or NE-28345, then the capsaicin, guaiacol, eugenol, Zingerone, civamide, nonivamide, nuvanil, olvanil, NE-19550, NE-21610, or NE-28345 are present in the composition in an amount 0.1%(w/v) to about 50% (w/v).
[0096] In an aspect, provided herein is a composition, comprising:
(i) a compound of structural Formula (I):
(R1)n2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨ORI4, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1-6 alkyl; and RIA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and (ii) a TrpV1 modulator;
wherein the compound of Formula (I), isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is not capsaicin; or wherein the TrpV1 modulator is not a fatty acid.
100971 In an aspect, provided herein is a composition, comprising:
(i) a compound of structural Formula (I):
(R1)2 = X R2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨ORI-, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1-6 alkyl; and RIP' is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
(ii) a TrpV1 modulator; and (iii) at least one excipient, wherein the compound of Formula (I), isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is not capsaicin; or wherein the TrpV1 modulator is not a fatty acid.
[0098] In some embodiments, the compound of Formula (I) is capsaicin. In some embodiments, the compound of Formula (I) is dihydrocapsaicin.
[0099] In some embodiments, the at least one TrpV1 modulator is a TrpV1 antagonist, a TrpV1 competitive agonist, or combination thereof.
[0100] In some embodiments, the at least one TrpV1 modulator is a triglyceride or spilanthol.
101011 In some embodiments, the at least one TrpV1 modulator is a fatty acid, triglyceride, or spilanthol.
[0102] In some embodiments, the fatty acid is a polyunsaturated fatty acid (PUFA).
[0103] In some embodiments, the fatty acid is a cannabinoid.
[0104] In some embodiments, the PUFA is anandamide.
[0105] In some embodiments, the PUFA is a cannabinoid.
[0106] In some embodiments, the fatty acid is an omega-9 fatty acid. In some embodiments, the fatty acid is an omega-3 fatty acid.
[0107] In some embodiments, the fatty acid is oleic acid or erucic acid.
[0108] In some embodiments, the at least one additional therapeutic agent is a FAAH receptor inhibitor.
101091 In some embodiments, the FAAH receptor inhibitor is SSR411298.
[0110] In some embodiments, the at least one additional therapeutic agent is a FAAH inhibitor.
[0111] In some embodiments, the FAAH inhibitor is a flavonoid. Exemplary flavonoids include, but are not limited to, myricetin, quercetin, kaempferol, luteolin, and apigenin.
In some embodiments, the FAAH inhibitor is kaempferol.
[0112] In some embodiments, the at least one additional therapeutic agent is an SPM.
[0113] In some embodiments, the SPM is maresin.
[0114] In some embodiments, the pharmaceutical composition is in a form for oral dosing or administration.
[0115] In some embodiments, the form is a suspension or a solution.
[0116] In some embodiments, the form is a solid dosage form.
101171 In some embodiments, the form is a tablet or a capsule.
[0118] In some embodiments, the pharmaceutical composition is in a form for inhalation, nebulization, or nasal delivery.
[0119] In some embodiments, the pharmaceutical composition is provided as an aerosol. In some embodiments, the pharmaceutical composition is provided as an inhalable aerosol. In some embodiments, the pharmaceutical composition is in a form of an electronic delivery system. In some embodiments, the pharmaceutical composition is a vaping device. In some embodiments, the pharmaceutical composition is provided as an e-cigarette.
[0120] In some embodiments, the pharmaceutical composition is in a form for inhalation administration or dosing by vaporizer.
[0121] In some embodiments, the pharmaceutical composition is in a form for parenteral administration or dosing.
101221 In some embodiments, the parenteral administration or dosing is injection, infusion, or implantation.
101231 In some embodiments, the injection is intravenous, intramuscular, subcutaneous, or intradermal.
[0124] In some embodiments, the pharmaceutical composition is in a form for dosing or administration by suppository.
[0125] In some embodiments, the pharmaceutical composition is in a form for cutaneous or transdermal administration.
[0126] In some embodiments, the pharmaceutical composition is in a form for sublingual or buccal administration.
[0127] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount less than about 10%, 5%, 2.5%, 1.0%, or 0.75% (w/v). In some embodiments, the compound of Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount in a range of about 0.5% to about 10%, about 0.5% to about 5%, about 1.0% to about 5%, or about 2.5% to about 4% (w/v).
[0128] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 0.1% (w/v).
[0129] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 1% (w/v).
[0130] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 10% (w/v).
[0131] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 20% (w/v).
[0132] In some embodiments, the compound of Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 30% (w/v).
[0133] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 40% (w/v).
[0134] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 0.1% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 1%
(w/v) to about 50%
(w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount less than about 10%, 5%, 2.5%, 1.0%, or 0.75% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount in a range of about 0.5% to about 10%, about 0.5% to about 5%, about 1.0% to about 5%, or about 2.5% to about 4% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 10% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt. solvate, or hydrate thereof is present in the composition in an amount of from about 15% (w/v) to about 50%
(w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 20% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 25% (w/v) to about 50%
(w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 30% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 35% (w/v) to about 50%
(w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 40% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 45% (w/v) to about 50%
(w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of about 10% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of about 15% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of about 20%
(w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of about 25% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of about 30% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of about 35%
(w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of about 40% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of about 45% (w/v). In some embodiments, the compound of Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of about 50%
(w/v).
[0135] In an aspect, provided herein is a composition, comprising:
(i) a compound of structural Formula (I):
( R.1) n2 = X R2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨ORIA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1-6 alkyl; and RIA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH,, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
(ii) a TrpV1 modulator; and (iii) at least one excipient, wherein the composition is formulated for dosing or delivery by enteral or parenteral administration [0136] In some embodiments, the composition is formulated as a liquid or a solid.
[0137] In some embodiments, the composition is formulated as a solid.
[0138] In some embodiments, the solid is a tablet, a capsule, a suppository, strip, or an implant.
101391 In some embodiments, the tablet is a dissolvable tablet or a bilayer tablet.
101401 In some embodiments, the strip is a dissolvable strip.
101411 In some embodiments, the composition is formulated as a liquid.
[0142] In some embodiments, the liquid is a solution, a suspension, an emulsion, a syrup, an elixir, a tincture, an ointment, a soft gel, an enema, foam, cream, lotion, or a gel.
[0143] In some embodiments, the composition is formulated for dosing or delivery by enteral administration.
[0144] In some embodiments, the enteral administration is oral or rectal administration.
[0145] In some embodiments, the composition is formulated for dosing or delivery by parenteral administration.
[0146] In some embodiments, the parenteral administration is sublingual administration, buccal administration, or administration by injection, infusion, implantation, or inhalation.
[0147] In an aspect, provided herein is a composition, comprising:
(i) a compound of structural Formula (1):
(R1) n2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨0RiA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1-6 alkyl; and RIA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
(ii) a TrpV1 modulator; and (iii) at least one excipient.
[0148] In some embodiments, the solid is a tablet, a capsule, a suppository, strip, or an implant.
[0149] In some embodiments, the tablet is a dissolvable tablet or a bilayer tablet.
101501 In some embodiments, the strip is a dissolvable strip.
101511 In an aspect, provided herein is a composition, comprising:
(i) a compound of structural Formula (I):
(R1)2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨ORIA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1_6 alkyl; and RiA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONE12, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
(ii) a TrpV1 modulator; and (iii) at least one excipient, wherein the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, and the TrpV1 modulator are released sequentially in any order or have different release profiles. In some embodiments, the co-formulated compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, and the TrpV1 modulator are administered sequentially. In some embodiments, the co-formulated compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, and the TrpV1 modulator are administered sequentially in a bilayer tablet. In some embodiments, the co-formulated compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, and the TrpV1 modulator have different release profiles, for example the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof or the TrpV1 modulator is released immediately and the other is an extended release.
101521 In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is released before the at least one additional therapeutic agent.
[0153] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is released after the at least one additional therapeutic agent.
[0154] In some embodiments, the solid is a tablet, a capsule, a suppository, strip, or an implant.
[0155] In some embodiments, the tablet is a dissolvable tablet or a bilayer tablet.
[0156] In some embodiments, the strip is a dissolvable strip.
[0157] In some embodiments, the compound of Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount less than about 10%, 5%, 2.5%, 1.0%, or 0.75% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount in a range of about 0.5% to about 10%, about 0.5% to about 5%, about 1.0% to about 5%, or about 2.5% to about 4% (w/v).
[0158] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 10% (w/v).
[0159] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 20% (w/v).
[0160] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 30% (w/v).
[0161] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 40% (w/v).
[0162] In some embodiments, the compound of Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 10% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 20% (w/v) to about 50%
(w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 30% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 40% (w/v) to about 50%
(w/v).
[0163] In some embodiments, the composition is a modified-release dosage form, a sustained-release dosage form, or a controlled-release dosage form.
[0164] In some embodiments, the composition is in modified-release dosage form.
[0165] In some embodiments, the modified-release dosage form is a delayed-release dosage form, an extended release dosage form, or a targeted release dosage form.
[0166] In some embodiments, the ratio of TrpV1 modulator to a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is about 1:1.
[0167] In some embodiments, the ratio of FAAH receptor inhibitor to a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is about 1:1.
[0168] In some embodiments, the ratio of SPM to a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is about 1:1.
[0169] In some embodiments, the composition is formulated as a pharmaceutical composition.
[0170] In some embodiments, the at least one excipient is at least one pharmaceutically acceptable excipient.
[0171] In some embodiments, the compound of structural Formula (I) has structural Formula (I-A):
R1.1 $0 R1.2--X
n1 0 n3 (I-A), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
1.1 ¨
_EC is hydrogen, halogen, ¨012.11A, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
T.1.2 I( is hydrogen, halogen, ¨0RI.2A, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and R1.1A and R1.2A are independently hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
101721 In some embodiments, It is CH3; and R'2 is OH.
a [0173] In some embodiments, X is 0. In some embodiments, X is NH. In some embodiments, = is a a double bond. In some embodiments, is a single bond. In some embodiments, n1 is 2. In some embodiments, n1 is 1. In some embodiments, n1 is 0. In some embodiments, R2 is unsubstituted alkyl. In some embodiments, R2 is ¨CH(CH3)2 or ¨CH3.
[0174] In some embodiments, the compound is at least one of:
H. HO
HO si HO
HO is HO
HO HO
is , or H0 si O
HO
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
[0175] In some embodiments, the compound is:
HO
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
[0176] In another aspect, provided herein is a supplement, comprising:
(i) a compound of structural Formula (I):
= x R2 ni 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨ORIA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1_6 alkyl; and A
KIis hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
(ii) at least one additional therapeutic agent selected from:
a fatty acid amide hydrolase (FAAH) receptor inhibitor, and a specialized pro-resolving mediator (SPM), or a combination thereof; and (iii) at least one excipient. In some embodiments, the supplement is in a form for oral dosing or administration (i . e. , ingestion).
[0177] In some embodiments, the compound of structural Formula (I) has structural Formula (I-A):
R1.1 Cr R1.2-' -.61 R2 X
n1 0 n3 (I-A), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
R" is hydrogen, halogen, WI-A, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R1.2 is hydrogen, halogen, ¨010.2A, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R11- and R12- are independently hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH,, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
[0178] In some embodiments, R" is CH3; and R12 is OH.
a [0179] In some embodiments, X is 0. In some embodiments, X is NH. In some embodiments, = is a a double bond. In some embodiments, is a single bond. In some embodiments, n1 is 2. In some embodiments, n1 is 1. In some embodiments, n1 is 0. In some embodiments, R2 is unsubstituted alkyl. In some embodiments, R2 is ¨CH(CH3)2 or ¨CH3.
[0180] In some embodiments, the compound is at least one of:
HO HO
HO HO el HO HO
HO
, or HO
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
[0181] In some embodiments, the compound is:
HO
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
[0182] In some embodiments, the at least one additional therapeutic agent is a TrpV1 modulator. In some embodiments, the at least one TrpV1 modulator is a partial agonist, antagonist, an inverse agonist, or combinations thereof. In some embodiments, the at least one TrpV1 modulator is a TrpV1 antagonist, a TrpV1 competitive agonist, or combination thereof.
[0183] Exemplary TrpV1 modulators include, but are not limited to, DHA
(docosahexaenoic acid), EPA (eicosapentaenoic acid), LNA (linolenic acid), LA (linoleic acid), petroselinic acid, or oleic acid, a-Linolenic acid, spilanthol, a FAHH receptor inhibitor, SSR411298, a maresin, a specialized proresolving mediators (SPM), anandamide, cannabinoids, oleoylethanolamide, olvanil, arvanil.
AM404, derivatives thereof, or combinations thereof.
[0184] In some embodiments, the at least one TrpV1 modulator is a partial agonist. Partial agonists comprise TrpV1 modulators that can activate the current through the ion channel. In some embodiments, the partial agonist comprises a fatty acid. In some embodiments, the partial agonist comprises a polyunsaturated fatty acid (PUFA). In some embodiments, the partial agonist comprises a n-3 PUFA. In some embodiments, the partial agonist comprises a n-6 PUFA. In some embodiments, the partial agonist comprises DHA (docosahexaenoic acid), EPA
(eicosapentaenoic acid), LNA (linolenic acid), LA (linoleic acid), or combinations thereof. In some embodiments, the partial agonist comprises a free fatty acid, ester, triglyceride, or combination thereof of DHA
(docosahexaenoic acid), EPA (eicosapentaenoic acid), LNA (linolenic acid), or LA (linoleic acid).
[0185] In some embodiments, the at least one TrpV1 modulator is an antagonist.
Antagonists comprise TrpV1 modulators that can inhibit the current evoked by an agonist.
In some embodiments, a partial agonist acts as an antagonist since by displacing an agonist in the same binding site. In some embodiments, the antagonist comprises a fatty acid. In some embodiments, the antagonist comprises a polyunsaturated fatty acid (PUFA). In some embodiments, the antagonist comprises a n-3 PUFA.
In some embodiments, the antagonist comprises a n-6 PUFA. In some embodiments, the antagonist comprises DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid), LNA
(linolenic acid), LA
(linoleic acid), petroselinic acid, oleic acid, or combinations thereof. In some embodiments, the antagonist comprises a free fatty acid, ester, triglyceride, or combination thereof of DHA
(docosahexaenoic acid), EPA (eicosapentaenoic acid), LNA (linolenic acid), LA
(linoleic acid), petroselinic acid, or oleic acid.
[0186] In some embodiments, the antagonist is a synthetic TrpV1 antagonist. In some embodiments, the TrpV1 antagonist does not cause hyperthermia. In some embodiments, the TrpV1 antagonist do not affect H+ activation of the channel. In some embodiments, the TrpV1 antagonist is PH
I
.N 0 N .
L
0 H r 1 0 I
,,,, t...- 'N 'eS- ri ii3O
,s, . .b F i ri , n"- N F ...."`" - -N' a H
I ,...- F F
---CI -F 0 N'"Igliv .F
n Os_s_f F .40 o F ¨F
o HN 'N C.
it. .
r...\ C
? \ , 1 NN'ir H
H
..---- CHNN. .="' '0 N=s,. ,...--. N. ,...--- ,or , 0 - ' 0 A
HO ,....,11 H
F
, 1 ,õ,...
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
[0187] In some embodiments, the at least one TrpV1 modulator is an inverse agonist. In some embodiments, the inverse agonist comprises a fatty acid. In some embodiments, the inverse agonist comprises a polyunsaturated fatty acid (PUFA). In some embodiments, the inverse agonist is anandamide. In some embodiments, the inverse agonist has a similar structure as anandamide. In some embodiments, the inverse agonist has a similar mechanism of action as anandamide. In some embodiments, the inverse agonist is a cannabinoid. Exemplary agents that have a similar structure, similar mechanism, or both include, but are not limited to, oleyethanolamide (OEA), olvanil, arvanil, and AM404.
[0188] In some embodiments, the at least one TrpV1 modulator is a fatty acid, triglyceride, or spilanthol.
[0189] In some embodiments, the fatty acid is a cannabinoid.
[0190] In some embodiments, the fatty acid is a polyunsaturated fatty acid (PUFA).
[0191] In some embodiments, the PUFA is anandamide.
[0192] In some embodiments, the PUFA is a cannabinoid.
[0193] In some embodiments, the fatty acid is an omega-9 fatty acid. In some embodiments, the fatty acid is an omega-3 fatty acid.
[0194] In some embodiments, the fatty acid is oleic acid or erucic acid.
101951 In some embodiments, the at least one additional therapeutic agent is a FAAH receptor inhibitor.
101961 In some embodiments, the FAAH receptor inhibitor is SSR411298.
[0197] In some embodiments, the at least one additional therapeutic agent is a FAAH inhibitor.
[0198] In some embodiments, the FAAH inhibitor is a flavonoid. Exemplary flavonoids include, but are not limited to, myricetin, quercetin, kaempferol, luteolin, and apigenin.
In some embodiments, the FAAH inhibitor is kaempferol.
[0199] In some embodiments, the at least one additional therapeutic agent is an SPM.
[0200] In some embodiments, the SPM is maresin.
[0201] In some embodiments, the supplement is in a form for oral dosing or administration. In some embodiments, the form is a suspension or a solution. In some embodiments, the form is a solid dosage form. In some embodiments, the solid dosage form is a tablet or a capsule.
[0202] In some embodiments, the supplement is in a form for inhalation, nebulization, or nasal delivery.
[0203] In some embodiments, the pharmaceutical composition is provided as an aerosol. In some embodiments, the pharmaceutical composition is provided as an inhalable aerosol. In some embodiments, the pharmaceutical composition is in a form of an electronic delivery system. In some embodiments, the pharmaceutical composition is a vaping device. In some embodiments, the pharmaceutical composition is provided as an e-cigarette.
[0204] In some embodiments, the supplement is in a form for inhalation administration or dosing by vaporizer.
[0205] In some embodiments, the supplement is in a form for parenteral administration or dosing.
[0206] In some embodiments, the administration or dosing is parenteral injection.
[0207] In some embodiments, the injection is intravenous, intramuscular, subcutaneous, or intradermal.
[0208] In some embodiments, the supplement is in a form for dosing or administration by suppository.
[0209] In some embodiments, the supplement is in a form for cutaneous or transdermal administration.
[0210] In some embodiments, the supplement is in a form for sublingual or buccal administration.
[0211] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount less than about 10%, 5%, 2.5%, 1.0%, or 0.75% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount in a range of about 0.5% to about 10%, about 0.5% to about 5%, about 1.0% to about 5%, or about 2.5% to about 4% (w/v).
102121 In some embodiments, the compound of Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 10% (w/v).
[0213] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 20% (w/v).
[0214] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 30% (w/v).
[0215] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 40% (w/v).
[0216] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 10% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 20% (w/v) to about 50%
(w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 30% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 40% (w/v) to about 50%
(w/v).
[0217] In some embodiments of the pharmaceutical compositions disclosed herein, the form is a suspension or a solution.
[0218] In some embodiments of the pharmaceutical compositions disclosed herein, the form is a tablet or a capsule.
[0219] In some embodiments of the pharmaceutical compositions disclosed herein, wherein the form is a tablet or a capsule, the tablet or capsule has an enteric coating.
[0220] In some embodiments of the pharmaceutical compositions disclosed herein, wherein the form is a tablet, the tablet is an osmotic floating tablet.
[0221] In some embodiments of the pharmaceutical compositions disclosed herein, wherein the form is a capsule, the capsule is a liquid-filled hard capsule.
[0222] In some embodiments of the pharmaceutical compositions disclosed herein, wherein the form is a capsule, the capsule is a soft gelatin capsule.
[0223] In some embodiments of the pharmaceutical compositions disclosed herein, the form is a modified-release dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the form is a modified-release dosage form, wherein the modified-release dosage form is a delayed-release dosage form, an extended-release (ER) dosage form, or a targeted-release dosage form. In some embodiments of the pharmaceutical compositions disclosed herein, wherein the form is an extended-release (ER) dosage form, the ER dosage form is a sustained-release (SR) dosage form or controlled-release (CR) dosage form.
[0224] In some embodiments of the pharmaceutical compositions disclosed herein, the form is an I.V. (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is from about 3.5 to about 14. In some embodiments of the pharmaceutical compositions disclosed herein, the form is an I.V. (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is from about 5.0 to about 12. In some embodiments of the pharmaceutical compositions disclosed herein, the form is an I.V. (i.e., infusion) dosage form. In some embodiments of the pharmaceutical composition, wherein the form is an IV. dosage form, the pH is from about 5.5 to about 11. In some embodiments of the pharmaceutical composition, wherein the form is an I.V.
dosage form, the pH is about 3.5. In some embodiments of the pharmaceutical composition, wherein the form is an I. V. dosage form, the pH is about 4Ø In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 4.5. In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 5Ø In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 5.5. In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 6Ø In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 6.5. In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 7Ø In some embodiments of the pharmaceutical composition, wherein the form is an 1.V.
dosage form, the pH is about 7.5. In some embodiments of the pharmaceutical composition, wherein the form is an I.V.
dosage form, the pH is about 8Ø In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 8.5. In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 9Ø In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 9.5. In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 10Ø In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 10.5. In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 11Ø In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 11.5. In some embodiments of the pharmaceutical composition, wherein the form is an I.V.
dosage form, the pH is about 12Ø In some embodiments of the pharmaceutical composition, wherein the form is an 1.V.
dosage form, the pH is about 12.5. In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 13Ø In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 13.5. In some embodiments of the pharmaceutical composition, wherein the form is an I.V. dosage form, the pH is about 14Ø
[0225] In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions are formulated for systemic delivery. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions are not formulated for local delivery. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions, when injected, result in a high level of systemic delivery or exposure without significant depot in the area of injection (i.e., do not provide a high local concentration of a compound of Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, and/or a TrpV1 modulator (e.g., TrpV1 inhibitor, TrpV1 antagonist, a TrpV1 competitive agonist.) In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical compositions, when injected, result in a high level of systemic delivery or exposure and are not significantly retained in the skin.
[0226] In some embodiments of the pharmaceutical compositions disclosed herein, wherein the form is a suspension or a solution, the dosage form comprises a co-solvent.
[0227] In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form comprises a co-solvent, the co-solvent comprises PEG200, PEG300, PEG400, PEG600, propylene glycol, ethanol, polysorbate 20, polysorbate 80, cremephor, glycerin, benzyl alcohol, dimethylacetamide (DMA), N-methy1-2-pyr.rolidone (NMP), tert-butanol, or combinations thereof.
[0228] In some embodiments of the pharmaceutical compositions disclosed herein, the dosage form further comprises an oil.
[0229] In some embodiments of the pharmaceutical compositions disclosed herein, wherein the dosage form further comprises an oil, the oil comprises sesame oil, soybean oil, vegetable oil, poppyseed oil, safflower oil, or combinations thereof.
[0230] The compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof of the present disclosure may be in the form of compositions suitable for administration to a subject. In general, such compositions are "pharmaceutical compositions"
comprising a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients. In certain embodiments, the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof are present in a therapeutically acceptable amount. The pharmaceutical compositions may be used in the methods of the present disclosure; thus, for example, the pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice the therapeutic and prophylactic methods and uses described herein.
102311 The pharmaceutical compositions of the present disclosure can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are set forth herein.
[0232] The pharmaceutical compositions containing the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof may be in a form suitable for oral use, for example, as tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads or elixirs.
Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents such as, for example, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets, capsules and the like contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture thereof. These excipients may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid;
binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
[0233] The tablets, capsules and the like suitable for oral administration may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by techniques known in the art to form osmotic therapeutic tablets for controlled release. Additional agents include biodegradable or biocompatible particles or a polymeric substance such as polyesters, polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides, polyglycolic acid, ethylene-vinylacetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide/glycolide copolymers, polylactide/glycolide copolymers, or ethylenevinylacetate copolymers in order to control delivery of an administered composition. For example, the oral agent can be entrapped in microcapsules prepared by coacervation techniques or by interfacial polymerization, by the use of hydroxymethyl cellulose or gelatin -microcapsules or poly(methylmethacrolate) microcapsules, respectively, or in a colloid drug delivery system. Colloidal dispersion systems include macromolecule complexes, nano-capsules, microspheres, microbeads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for the preparation of the above-mentioned formulations will be apparent to those skilled in the art.
[0234] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
[0235] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture thereof. Such excipients can be suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, for example a naturally-occurring phosphatide (e.g., lecithin), or condensation products of an alkylene oxide with fatty acids (e.g., polvoxv-ethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., for heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives.
[0236] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
[0237] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, and optionally one or more suspending agents and/or preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.
[0238] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example, liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example, gum acacia or gum tragacanth; naturally occurring phosphatides, for example, soybean, lecithin, and esters or partial esters derived from fatty acids;
hexitol anhydrides, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, for example, polyoxyethylene sorbi tan monooleate.
[0239] The pharmaceutical compositions typically comprise a therapeutically effective amount of a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically and physiologically acceptable formulation agents. Suitable pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methyl parabens, ethyl or n-propyl, p-hydroxybenzoate), emulsifying agents, suspending agents, dispersing agents, solvents, fillers, bulking agents, detergents, buffers, vehicles, diluents, and/or adjuvants. For example, a suitable vehicle may be physiological saline solution or citrate-buffered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art will readily recognize a variety of buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein.
Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. As an example, the buffer components can be water soluble materials such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Acceptable buffering agents include, for example, a Tris buffer; N-(2-Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES); 2-(N-Morpholino)ethanesulfonic acid (MES); 2-(N-Morpholino)ethanesulfonic acid sodium salt (MES); 3-(N-Morpholino)propanesulfonic acid (MOPS); and N-tris[Hydroxymethyllmethyl-3-aminopropanesulfonic acid (TAPS).
[0240] After a pharmaceutical composition has been formulated, it may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored either in a ready-to-use form, a lyophilized form requiring reconstitution prior to use, a liquid form requiring dilution prior to use, or other acceptable form. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, ampule, syringe, or autoinjector (similar to, e.g., an EpiPen0)), whereas a multi-use container (e.g., a multi-use vial) is provided in other embodiments.
[0241] Formulations can also include carriers to protect the composition against rapid degradation or elimination from the body, such as a controlled release formulation, including liposomes, hydrogels, prodrugs and microencapsulated delivery systems. For example, a time-delay material such as glyceryl monostearate or glyceryl stearate alone, or in combination with a wax, may be employed.
Any drug delivery apparatus may be used to deliver a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof, including implants (e.g., implantable pumps) and catheter systems, slow injection pumps and devices, all of which are well known to the skilled artisan.
[0242] Depot injections, which are generally administered subcutaneously or intramuscularly, may also be utilized to release the compound (e.g., a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof) disclosed herein over a defined period of time.
Depot injections are usually either solid- or oil-based and generally comprise at least one of the formulation components set forth herein. One of ordinary skill in the art is familiar with possible formulations and uses of depot injections.
[0243] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents mentioned herein.
The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butane diol.
Acceptable diluents, solvents and dispersion media that may be employed include water, Ringer's solution, isotonic sodium chloride solution, Cremophor EL (BASF, Parsippany, NJ) or phosphate buffered saline (PBS), ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium; for this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides. Moreover, fatty acids, such as oleic acid, find use in the preparation of injectables. Prolonged absorption of particular injectable formulations can be achieved by including an agent that delays absorption (e.g., aluminum monostearate or gelatin).
[0244] The present disclosure contemplates the administration of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof in the form of suppositories for rectal administration. The suppositories can be prepared by mixing the drug with a suitable non-irritating excipient, which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter and polyethylene glycols.
[0245] The compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof may be in the form of any other suitable pharmaceutical composition (e.g., sprays for nasal or inhalation use) currently known or developed in the future Methods of Use [0246] In an aspect, provided herein is a method of inhibiting mitochondrial complex I, comprising contacting the mitochondrial complex 1 with a compound of structural Formula (1):
(R1)2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
R' is independently hydrogen, halogen, ¨OR' A, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1-6 alkyl; and RiA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONW, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
[0247] In some embodiments, the compound of structural Formula I has the structure:
HO
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
[0248] In some embodiments, at least 10 viM of a compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used in the method of inhibiting mitochondrial complex I. In some embodiments, at least 15 p.M of a compound of structural Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used in the method of inhibiting mitochondrial complex I. In some embodiments, at least 20 p.M of a compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used in the method of inhibiting mitochondrial complex I. In some embodiments, at least 25 "AM of a compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used in the method of inhibiting mitochondrial complex I. In some embodiments, at least 30 uM of a compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used in the method of inhibiting mitochondrial complex I. In some embodiments, at least 35 1,04 of a compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used in the method of inhibiting mitochondri al complex I. In some embodiments, at least 40 uM of a compound of structural Formula (I), or an isotopic van i ant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used in the method of inhibiting mitochondrial complex I. In some embodiments, at least 45 uM of a compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used in the method of inhibiting mitochondrial complex I. In some embodiments, at least 45 uM of a compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used in the method of inhibiting mitochondrial complex I. In some embodiments, at least 50 uM of a compound of structural Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is used in the method of inhibiting mitochondrial complex I.
[0249] In an aspect, provided herein is a method of a method of treating and/or preventing a capsaicin-responsive disease or disorder, comprising administering to a subject in need thereof a pharmaceutical composition or a supplement (e.g., a nutritional supplement) as disclosed herein.
[0250] In some embodiments, the disease or disorder is a cell proliferative disease, obesity, diabetes, a bacterial infection, a cardiovascular disease, a neurodegenerative disease or disorder, an inflammatory disease or disorder, a comorbidity, an autoimmune disease, hypercholesterolemia or a mood disorder. In some embodiments, the disease or disorder is an infectious disease or disorder (e.g., influenza or coronavirus). In some embodiments, the disease or disorder is a coagulant disease or disorder.
[0251] In some embodiments, the mood disorder is depression. In some embodiments, the inflammatory disease or disorder is rheumatoid arthritis. In some embodiments, the cell proliferative disease is a cancer. In some embodiments, the disorder is diabetes or obesity.
In some embodiments, the comorbidity is chronic kidney disease, stroke, congestive heart failure, dementia, schizophrenia, hepatitis, autism spectrum disorder, HIV, or a combination thereof.
[0252] In some embodiments, the supplements disclosed herein are for use in the treatment of a capsaicin-responsive disease or disorder.
[0253] In some embodiments, the supplements disclosed herein are for use in the treatment of obesity, diabetes, a bacterial infection, a cardiovascular disease, a neurodegenerative disease or disorder, an inflammatory disease or disorder, a comorbidity, an autoimmune disease, hypercholesterolemia or a mood disorder. In some embodiments, the supplements disclosed herein are used as an anti-coagulant. In some embodiments, the supplements disclosed herein are used for supporting the cognitive health of a human. In some embodiments, the supplements disclosed herein are used for supporting clarity and/or concentration of a human. In some embodiments, the supplements disclosed herein are used for promoting the longevity of a human.
In some embodiments, the supplements disclosed herein are used for boosting alertness or wakefulness of a human. In some embodiments, the supplements disclosed herein are used for supporting a healthy weight in a human. In some embodiments, the supplements disclosed herein are used for promoting the microbiome health of a human. In some embodiments, the supplements disclosed herein are used muscle energetic enhancers of a human.
[0254] In some embodiments, the mood disorder is depression. In some embodiments, the inflammatory disease or disorder is rheumatoid arthritis. In some embodiments, the cell proliferative disease is a cancer. In some embodiments, the disorder is diabetes or obesity.
[0255] In some embodiments, administration of the pharmaceutical compositions or supplements disclosed herein reduces fibrosis. In some embodiments, administration of the pharmaceutical composition or supplements disclosed herein decreases hepatic steatosis. In some embodiments, administration of the pharmaceutical composition or supplements disclosed herein decreases stellate cell activation. In some embodiments, administration of the pharmaceutical composition or supplements disclosed herein reduces body fat. In some embodiments, administration of the pharmaceutical composition or supplements disclosed herein reduces the percent of body fat as compared to body weight. In some embodiments, administration of the pharmaceutical composition or supplements disclosed herein decreases glucose levels. In some embodiments, administration of the pharmaceutical composition or supplements disclosed herein decreases fasting glucose levels. In some embodiments, administration of the pharmaceutical composition or supplements disclosed herein reduces capasacinoid-induced TRPV1 signaling. In some embodiments, the reduction is by at least or about 0.5X, 1.0X, 1.5X, 2.0X, 2.5X, 3.0X, 5X, 10X, or more than 10X.
[0256] In an aspect, provided herein is a method of treating or preventing a capsaicin-responsive disease or disorder, comprising administering to a subject in need thereof:
(i) a compound of structural Formula (I):
n1 o n3 (T), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
RI is independently hydrogen, halogen, ¨ORI", substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is substituted or unsubstituted C1-6 alkyl; and RiA is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroallcyl; and (ii) at least one additional therapeutic agent selected from:
a transient receptor potential cation channel subfamily V member 1 (TrpV1) modulator, a fatty acid amide hydrolase (FAAH) receptor inhibitor; and a specialized pro-resolving mediator (SPM), or a combination thereof, wherein when the TrpV1 modulator is a fatty acid, then the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, and the TrpV1 modulator are each individually formulated.
102571 In some embodiments, R" is CH3; and R1.2 is OH.
a [0258] In some embodiments, X is 0. In some embodiments, X is NH. In some embodiments, = is a a double bond. In some embodiments, = is a single bond. In some embodiments, n1 is 2. In some embodiments, n1 is 1. In some embodiments, n1 is 0. In some embodiments, R2 is unsubstituted alkyl. In some embodiments, R2 is ¨CH(CH3)2 or ¨CH3.
[0259] In some embodiments, the compound is at least one of:
HO HO
HO HO
HO HO =
HO HO
HO si , or HO Is or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
[0260] In some embodiments, the compound is:
HO
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
[0261] In some embodiments, the TrpV1 modulator is derived from a foodstuff, foodstuff extract, a fruit extract, a vegetable extract, and/or a plant extract including but not limited to almonds, avocado, and/or olive oil.
[0262] In an aspect, provided herein is a method of treating a capsaicin-responsive disease or disorder, comprising subjecting a patient in need thereof to cryotherapy and administering a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
[0263] In an aspect, provided herein is a method of treating a capsaicin-responsive disease or disorder, comprising to a subject in need thereof a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, and milk, or a milk-derived product including but not limited to casein. In an aspect, provided herein is a method of treating a capsaicin-responsive disease or disorder, comprising to a subject in need thereof a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, and peanuts, or a peanut-derived product including but not limited to peanut butter.
[0264] In some embodiments, the at least one additional therapeutic agent is a TrpV1 modulator.
[0265] In some embodiments, the TrpV1 modulator is a TrpV1 antagonist, a TrpV1 competitive agonist, or combination thereof.
[0266] In some embodiments, the TrpV1 modulator is a fatty acid triglyceride, or spilanthol.
[0267] In some embodiments, the fatty acid is a cannabinoid.
[0268] In some embodiments, the fatty acid is a polyunsaturated fatty acid (PUFA).
[0269] In some embodiments, the PUFA is anandamide.
[0270] In some embodiments, the PUFA is a cannabinoid.
[0271] In some embodiments, the fatty acid is an omega-9 fatty acid. In some embodiments, the fatty acid is an omega-3 fatty acid.
[0272] In some embodiments, the fatty acid is oleic acid or erucic acid. In some embodiments, the fatty acid is oleic acid.
[0273] In some embodiments, the fatty acid is eicosapentanenoic acid (EPA). In some embodiments the fatty acid is docosahexaenoic acid (DHA).
102741 In some embodiments, the at least one additional therapeutic agent is a FAAH receptor inhibitor.
102751 In some embodiments, the FAAH receptor inhibitor is SSR411298.
[0276] In some embodiments, the at least one additional therapeutic agent is a FAAH inhibitor.
[0277] In some embodiments, the FAAH inhibitor is a flavonoid. Exemplary flavonoids include, but are not limited to, myricetin, quercetin, kaempferol, luteolin, and apigenin.
In some embodiments, the FAAH inhibitor is kaempferol.
[0278] In some embodiments, the at least one additional therapeutic agent is an SPM.
[0279] In some embodiments, the SPM is maresin.
[0280] In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally.
[0281] In some embodiments, the compound of structural Formula (1) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally via a suspension or solution.
[0282] In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally via a solid dosage form. In some embodiments, the solid dosage form is a tablet or capsule.
[0283] In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by inhalation, nebulization, or nasal delivery.
[0284] In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is provided as an aerosol. In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is provided as an inhalable aerosol. In some embodiments, the compound of structural Formula (1) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is in a form of an electronic delivery system. In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is administered using a vaping device. In some embodiments, the compound of structural Formula (1) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered using an e-cigarette.
[0285] In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by inhalation via a vaporizer.
[0286] In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered parenterally.
[0287] In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered via parenteral injection, infusion, or implantation.
[0288] In some embodiments, the parenteral injection is intravenous, intramuscular, subcutaneous, or intradermal.
[0289] In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered via a suppository.
[0290] In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered cutaneous or transdermal delivery.
[0291] In some embodiments, the compound of structural Formula (I) or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by sublingual or buccal delivery.
[0292] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount less than about 10%, 5%, 2.5%, 1.0%, or 0.75% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount in a range of about 0.5% to about 10%, about 0.5% to about 5%, about 1.0% to about 5%, or about 2.5% to about 4% (w/v).
[0293] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 10% (w/v).
[0294] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 20% (w/v).
[0295] In some embodiments, the compound of Formula (1), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 30% (w/v).
[0296] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 40% (w/v).
[0297] In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 10% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 20% (w/v) to about 50%
(w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 30% (w/v) to about 50% (w/v). In some embodiments, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 40% (w/v) to about 50%
(w/v).
[0298] In some embodiments, the ratio of the therapeutic agent to a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is about 1:1. In some embodiments, the ratio of the therapeutic agent to a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is about 1.1:1. In some embodiments, the ratio of the therapeutic agent to a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is about 1.2:1. In some embodiments, the ratio of the therapeutic agent to a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is about 1.3:1. In some embodiments, the ratio of the therapeutic agent to a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is about 1.4:1. In some embodiments, the ratio of the therapeutic agent to a compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is about 1.5:1.
[0299] In some embodiments, the disease or disorder is a cell proliferative disease, obesity, diabetes, a bacterial infection, a cardiovascular disease, a neurodegenerative disease or disorder, an inflammatory disease or disorder, a comorbidity, an autoimmune disease, hypercholesterolemia or a mood disorder. In some embodiments, the mood disorder is depression. In some embodiments, the inflammatory disease or disorder is rheumatoid arthritis. In some embodiments, the cell proliferative disease is a cancer. In some embodiments, the disorder is diabetes or obesity.
[0300] In some embodiments, the compound of Formula (1), or a pharmaceutically acceptable salt thereof, and the at least one additional therapeutic agent are administered simultaneously, approximately simultaneously, or sequentially, in any order.
[0301] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the at least one additional therapeutic agent are administered simultaneously or approximately simultaneously.
[0302] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the at least one additional therapeutic agent are administered sequentially.
[0303] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is released before the at least one additional therapeutic agent.
[0304] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is released after the at least one additional therapeutic agent [0305] In some embodiments of the methods described herein, the compound of Formula I, or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof, is administered to the subject daily.
[0306] In some embodiments of the methods described herein, the compound of Formula I, or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof, is administered to the subject once per day, twice per day, three times per day, or four times per day.
[0307] In some embodiments of the methods described herein, the compound of Formula 1, or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof, is administered to the subject for a period of at least one week.
[0308] In some embodiments of the methods described herein, the compound of Formula I, or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof, is administered to the subject for a period of one week, two weeks, 6 weeks, 12 weeks, 24 weeks, 48 weeks, or 52 weeks.
Dosing [0309] In some embodiments, the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof pharmaceutical compositions described herein are provided at the maximum tolerated dose (MTD) for the compound of Formula (I). In other embodiments, the amount of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof pharmaceutical composition administered is from about 10% to about 90% of the maximum tolerated dose (MTD), from about 25% to about 75% of the MTD, or about 50% of the MTD. In some other embodiments, the amount of the compound of Formula (1) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof pharmaceutical compositions administered is from about 0.1%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or higher, or any range derivable therein, of the MTD for the compound of Formula (I). Percentage can be weight by weight or weight by volume.
[0310] In certain embodiments, in the treatment, prevention, or amelioration of one or more symptoms of the disorders, diseases, or conditions described herein, an appropriate dosage level of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof generally is ranging from about 1 to 8000 mg, from about 1 to about 1000 mg, from about 5 to about 1000 mg, from about 5 to about 800 mg, from about 5 to about 600 mg, from about 5 to about 500 mg or from about 50 to about 500 mg which can be administered in single or multiple doses. In certain embodiments, the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 240, about 250, about 260, about 270, about 275, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000, about 1200, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, about 2400, about 2500, about 2600, about 2800, about 3000, about 4000, about 5000, about 6000, about 7000, about 8000 mg, or any range derivable therein.
[0311] In certain embodiments, the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 275 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000, about 1200, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, about 2400, about 2500, about 2600, about 2800, about 3000, about 4000, about 5000, about 6000, about 7000, about 8000 mg mg/day.
103121 For oral administration, the pharmaceutical compositions provided herein can be formulated in the form of tablets or capsules containing from about 1.0 to about 1,000 mg of a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof, in one embodiment, 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg. about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, or about 2000 mg of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof for the symptomatic adjustment of the dosage to the patient to be treated.
[0313] In some embodiments, the compound of Formula (I) or a hydrate, solvate.
tautomer, or pharmaceutically acceptable salt thereof is administered in an amount of about or at most 1 mg/day, about 5 mg/day, about 10 mg/day, about 15 mg/day, about 20 mg/day, about 25 mg/day, about 30 mg/day, about 35 mg/day, about 40 mg/day, about 45 mg/day, about 50 mg/day, about 55 mg/day, about 60 mg/day, about 65 mg/day, about 70 mg/day, about 75 mg/day, about 80 mg/day, about 85 mg/day, about 90 mg/day, about 95 mg/day, about 100 mg/day, about 105 mg/day, about 110 mg/day, about 115 mg/day, about 120 mg/day, about 125 mg/day, about 130 mg/day, about 135 mg/day, about 140 mg/day, about 145 mg/day, about 150 mg/day, about 155 mg/day, about 160 mg/day, about 170 mg/day, about 180 mg/day, about 190 mg/day, about 200 mg/day, about 210 mg/day, about 220 mg/day, about 230 mg/day, about 240 mg/day, about 250 mg/day, about 260 mg/day, about 270 mg/day, about 280 mg/day, about 290 mg/day, about 300 mg/day, about 310 mg/day, about 320 mg/day, about 330 mg/day, about 340 mg/day, about 350 mg/day, about 360 mg/day, about 370 mg/day, about 380 mg/day, about 390 mg/day, about 400 mg/day, 410 mg/day, about 420 mg/day, about 430 mg/day, about 440 mg/day, about 450 mg/day, about 460 mg/day, about 470 mg/day, about 480 mg/day, about 490 mg/day, about 500 mg/day, about 510 mg/day, about 520 mg/day, about 530 mg/day, about 540 mg/day, about 550 mg/day, about 560 mg/day, about 570 mg/day, about 580 mg/day, about 590 mg/day, or about 600 mg/day. In some embodiments, the compound of Formula (I) is administered in a range of about 1 mg/day to about 20 mg/day, about 1 mg/day to about 50 mg/day about 1 mg/day to about 100 mg/day, about 10 mg/day to about 100 mg/day, about 50 mg/day to about 500 mg/day, about 50 mg/day to about 250 mg/day, about 100 mg/day to about 500 mg/day or about 100 mg/day to about 200 mg/day.
[0314] In some embodiments, the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof is derived from a natural source such that about or at most 1 mg/day, about 5 mg/day, about 10 mg/day, about 15 mg/day, about 20 mg/day, about 25 mg/day, about 30 mg/day, about 35 mg/day, about 40 mg/day, about 45 mg/day, about 50 mg/day, about 55 mg/day, about 60 mg/day, about 65 mg/day, about 70 mg/day, about 75 mg/day, about 80 mg/day, about 85 mg/day, about 90 mg/day, about 95 mg/day, about 100 mg/day, about 105 mg/day, about 110 mg/day, about 115 mg/day, about 120 mg/day, about 125 mg/day, about 130 mg/day, about 135 mg/day, about 140 mg/day, about 145 mg/day, about 150 mg/day, about 155 mg/day, about 160 mg/day, about 170 mg/day, about 180 mg/day, about 190 mg/day, about 200 mg/day, about 210 mg/day, about 220 mg/day, about 230 mg/day, about 240 mg/day, about 250 mg/day, about 260 mg/day, about 270 mg/day, about 280 mg/day, about 290 mg/day, about 300 mg/day, about 310 mg/day, about 320 mg/day, about 330 mg/day, about 340 mg/day, about 350 mg/day, about 360 mg/day, about 370 mg/day, about 380 mg/day, about 390 mg/day, about 400 mg/day, 410 mg/day, about 420 mg/day, about 430 mg/day, about 440 mg/day, about 450 mg/day, about 460 mg/day, about 470 mg/day, about 480 mg/day, about 490 mg/day, about 500 mg/day, about 510 mg/day, about 520 mg/day, about 530 mg/day, about 540 mg/day, about 550 mg/day, about 560 mg/day, about 570 mg/day, about 580 mg/day, about 590 mg/day, or about 600 mg/day Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof is administered. For example, Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof is derived from chili, cayenne pepper, red pepper, oleoresin red pepper, tomato, or combinations thereof In some embodiments, Formula (1) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof is derived from Capsicum Frutescens or Oleoresin Capsicum.
103151 In some embodiments, the natural source comprises at least or about 1 mg/g, about 5 mg/g, about 10 mg/g, about 15 mg/g, about 20 mg/g, about 25 mg/g, about 30 mg/g, about 35 mg/g, about 40 mg/g, about 45 mg/g, about 50 mg/g, about 55 mg/g, about 60 mg/g, about 65 mg/g, about 70 mg/g, about 75 mg/g, or about 80 mg/g of a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the natural source comprises at least or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than 95% of a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof.
[0316] In some embodiments, various heat units of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof is administered. In some embodiments, the compound of Formula (1) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof comprises a Scoville Heat Unit (SHU) of about 0 to about 16 M SHU. In some embodiments, the compound of Formula (1) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof comprises a Scoville Heat Unit (SHU) of at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, or more than 16 M SHU. SHU, in some embodiments, provides the amount of sugar water to dilute a volume of pepper extract. For example, 100 SHU indicates that 100 mL
of sugar water is needed to dilute 1 mL of pepper extract.
[0317] In certain embodiments, in the treatment, prevention, or amelioration of one or more symptoms of the disorders, diseases, or conditions described herein, an appropriate dosage level of the compound of oleic acid or a pharmaceutically acceptable salt thereof generally is ranging from about 1 to 12000 mg, from about 1000 to 12000 mg, about 2000 to 12000 mg, about 3000 to 12000 mg about 4000 to 12000 mg, about 5000 to 12000 mg, about 6000 to 12000 mg, about 1000 to 11000 mg, about 1000 to 10000 mg, about 1000 to 9000 mg, about 1000 to 8000 mg, or about 1000 to 7000 mg, which can be administered in single or multiple doses. In certain embodiments, the oleic acid or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000mg or any range derivable therein.
[0318] In certain embodiments, the oleic acid, or pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg_ about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 275 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000, about 1200, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, about 2400. about 2500, about 2600, about 2800, about 3000, about 4000, about 5000, about 6000, about 7000, about 8000 mg mg/day. 1000 to 12000mg, about 2000 to 12000 mg, about 3000 to 12000 mg about 4000 to 12000 mg, about 5000 to 12000 mg, about 6000 to 12000 mg, about 1000 to 11000 mg, about 1000 to 10000 mg, about 1000 to 9000 mg, about 1000 to 8000 mg, or about 1000 to 7000 mg, which can be administered in single or multiple doses. In certain embodiments, the oleic acid or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000mg or any range derivable therein.
[0319] For oral administration, the pharmaceutical compositions provided herein can be formulated in the form of tablets or capsules containing from about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000mg of the compound of oleic acid or a pharmaceutically acceptable salt thereof for the symptomatic adjustment of the dosage to the patient to be treated.
[0320] In some embodiments, the oleic acid, or pharmaceutically acceptable salt thereof is administered in an amount of about or at most about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000 mg or any range derivable therein. In some embodiments, the oleic acid is administered in a range of about 1000 to 12000 mg/day, about 2000 to 12000 mg/day, about 3000 to 12000 mg/day about 4000 to 12000 mg/day, about 5000 to 12000 mg/day, about 6000 to 12000 mg/day, about 1000 to 11000 mg/day, about 1000 to 10000 mg/day, about 1000 to 9000 mg/day, about 1000 to 8000 mg/day, or about 1000 to 7000 mg/day. In some embodiments, the oleic acid or pharmaceutically acceptable salt thereof is derived from a natural source such that about or at most about 1 mg/day, about 10 mg/day, about 50 mg/day, about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 800 mg/day, about 900 mg/day, about 1000 mg/day, about 1100 mg/day, about 1200 mg/day, about 1300 mg/day, about 1400 mg/day, about 1500 mg/day, about 1600 mg/day, about 1700 mg/day, about 1800 mg/day, about 1900 mg/day, about 2000 mg/day, about 2100 mg/day, about 2200 mg/day, about 2300 mg/day, about 2400 mg/day, about 2500 mg/day, about 2600 mg/day, about 2700 mg/day, about 2800 mg/day, about 2900 mg/day, about 3000 mg/day, about 3100 mg/day, about 3200 mg/day, about 3300 mg/day, about 3400 mg/day, about 3500 mg/day, about 3600 mg/day, about 3700 mg/day, about 3800 mg/day, about 3900 mg/day, about 4000 mg/day, about 4100 mg/day, about 4200 mg/day, about 4300 mg/day, about 4400 mg/day, about 4500 mg/day, about 4600 mg/day, about 4700 mg/day, about 4800 mg/day, about 4900 mg/day. about 5000 mg/day about 5100 mg/day, about 5200 mg/day, about 5300 mg/day, about 5400 mg/day_ about 5500 mg/day, about 5600 mg/day, about 5700 mg/day, about 5800 mg/day, about 5900 mg/day, about 6000 mg/day, about 6100 mg/day, about 6200 mg/day, about 6300 mg/day, about 6400 mg/day, about 6500 mg/day, about 6600 mg/day, about 6700 mg/day, about 6800 mg/day, about 6900 mg/day, about 7000 mg/day, about 7100 mg/day, about 7200 mg/day, about 7300 mg/day, about 7400 mg/day, about 7500 mg/day, about 7600 mg/day, about 7700 mg/day, about 7800 mg/day, about 7900 mg/day, about 8000 mg/day, about 8100 mg/day, about 8200 mg/day, about 8300 mg/day, about 8400 mg/day, about 8500 mg/day, about 8600 mg/day, about 8700 mg/day, about 8800 mg/day, about 8900 mg/day, about 9000 mg/day, about 9100 mg/day, about 9200 mg/day, about 9300 mg/day, about 9400 mg/day, about 9500 mg/day, about 9600 mg/day, about 9700 mg/day, about 9800 mg/day, about 9900 mg/day, or about 10000 mg/day, about 10100 mg/day, about 10200 mg/day, about 10300 mg/day, about 10400 mg/day, about 10500 mg/day, about 10600 mg/day, about 10700 mg/day, about 10800 mg/day, about 10900 mg/day, about 11000 mg/day about 11100 mg/day, about 11200 mg/day, about 11300 mg/day, about 11400 mg/day, about 11500 mg/day, about 11600 mg/day, about 11700 mg/day, about 11800 mg/day, about 11900 mg/day, or about 12000mg/day oleic acid or pharmaceutically acceptable salt thereof is administered.
[0321] In some embodiments, the natural source comprises at least or about 1 mg/g, about 5 mg/g, about 10 mg/g, about 15 mg/g, about 20 mg/g, about 25 mg/g, about 30 mg/g, about 35 mg/g, about 40 mg/g, about 45 mg/g, about 50 mg/g, about 55 mg/g, about 60 mg/g, about 65 mg/g, about 70 mg/g, about 75 mg/g, or about 80 mg/g of oleic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the natural source comprises at least or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than 95% of a compound of oleic acid or pharmaceutically acceptable salt thereof.
[0322] In certain embodiments, in the treatment, prevention, or amelioration of one or more symptoms of the disorders, diseases, or conditions described herein, an appropriate dosage level of the compound of EPA or a pharmaceutically acceptable salt thereof generally is ranging from about 1 to 12000 mg, from about 1000 to 12000mg, about 2000 to 12000 mg, about 3000 to 12000 mg about 4000 to 12000 mg, about 5000 to 12000 mg, about 6000 to 12000 mg, about 1000 to 11000 mg, about 1000 to 10000 mg, about 1000 to 9000 mg, about 1000 to 8000 mg, or about 1000 to 7000 mg, which can be administered in single or multiple doses. In certain embodiments, the EPA or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000mg or any range derivable therein.
[0323] In certain embodiments, the EPA, or pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 275 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000, about 1200, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, about 2400, about 2500_ about 2600, about 2800, about 3000, about 4000, about 5000, about 6000, about 7000, about 8000 mg mg/day. 1000 to 12000mg, about 2000 to 12000 mg, about 3000 to 12000 mg about 4000 to 12000 mg, about 5000 to 12000 mg, about 6000 to 12000 mg, about 1000 to 11000 mg, about 1000 to 10000 mg, about 1000 to 9000 mg, about 1000 to 8000 mg, or about 1000 to 7000 mg, which can be administered in single or multiple doses. In certain embodiments, the EPA or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000mg or any range derivable therein.
[0324] For oral administration, the pharmaceutical compositions provided herein can be formulated in the form of tablets or capsules containing from about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000mg of the compound of EPA or a pharmaceutically acceptable salt thereof for the symptomatic adjustment of the dosage to the patient to be treated.
[0325] In some embodiments, the EPA, or pharmaceutically acceptable salt thereof is administered in an amount of about or at most about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000 mg or any range derivable therein. In some embodiments, the EPA is administered in a range of about 1000 to 12000 mg/day, about 2000 to 12000 mg/day, about 3000 to 12000 mg/day about 4000 to 12000 mg/day, about 5000 to 12000 mg/day, about 6000 to 12000 mg/day, about 1000 to 11000 mg/day, about 1000 to 10000 mg/day, about 1000 to 9000 mg/day, about 1000 to 8000 mg/day, or about 1000 to 7000 mg/day. In some embodiments, the EPA or pharmaceutically acceptable salt thereof is derived from a natural source such that about or at most about 1 mg/day, about 10 mg/day, about 50 mg/day, about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 800 mg/day, about 900 mg/day, about 1000 mg/day, about 1100 mg/day, about 1200 mg/day, about 1300 mg/day, about 1400 mg/day, about 1500 mg/day, about 1600 mg/day, about 1700 mg/day, about 1800 mg/day, about 1900 mg/day, about 2000 mg/day, about 2100 mg/day, about 2200 mg/day, about 2300 mg/day, about 2400 mg/day, about 2500 mg/day, about 2600 mg/day, about 2700 mg/day, about 2800 mg/day, about 2900 mg/day, about 3000 mg/day, about 3100 mg/day, about 3200 mg/day, about 3300 mg/day, about 3400 mg/day, about 3500 mg/day, about 3600 mg/day, about 3700 mg/day, about 3800 mg/day, about 3900 mg/day, about 4000 mg/day, about 4100 mg/day, about 4200 mg/day, about 4300 mg/day, about 4400 mg/day, about 4500 mg/day, about 4600 mg/day, about 4700 mg/day, about 4800 mg/day, about 4900 mg/day, about 5000 mg/day about 5100 mg/day, about 5200 mg/day, about 5300 mg/day, about 5400 mg/day, about 5500 mg/day, about 5600 mg/day, about 5700 mg/day, about 5800 mg/day, about 5900 mg/day, about 6000 mg/day, about 6100 mg/day, about 6200 mg/day, about 6300 mg/day, about 6400 mg/day, about 6500 mg/day, about 6600 mg/day, about 6700 mg/day, about 6800 mg/day, about 6900 mg/day, about 7000 mg/day, about 7100 mg/day, about 7200 mg/day, about 7300 mg/day, about 7400 mg/day, about 7500 mg/day, about 7600 mg/day, about 7700 mg/day, about 7800 mg/day, about 7900 mg/day, about 8000 mg/day, about 8100 mg/day, about 8200 mg/day, about 8300 mg/day, about 8400 mg/day, about 8500 mg/day, about 8600 mg/day, about 8700 mg/day, about 8800 mg/day, about 8900 mg/day, about 9000 mg/day, about 9100 mg/day, about 9200 mg/day, about 9300 mg/day, about 9400 mg/day, about 9500 mg/day, about 9600 mg/day, about 9700 mg/day, about 9800 mg/day, about 9900 mg/day, or about 10000 mg/day, about 10100 mg/day, about 10200 mg/day, about 10300 mg/day, about 10400 mg/day, about 10500 mg/day, about 10600 mg/day, about 10700 mg/day, about 10800 mg/day, about 10900 mg/day, about 11000 mg/day about 11100 mg/day, about 11200 mg/day, about 11300 mg/day, about 11400 mg/day, about 11500 mg/day, about 11600 mg/day, about 11700 mg/day, about 11800 mg/day, about 11900 mg/day, or about 12000mg/day EPA or pharmaceutically acceptable salt thereof is administered.
103261 In some embodiments, the natural source comprises at least or about 1 mg/g, about 5 mg/g, about 10 mg/g, about 15 mg/g, about 20 mg/g, about 25 mg/g, about 30 mg/g, about 35 mg/g, about 40 mg/g, about 45 mg/g, about 50 mg/g, about 55 mg/g, about 60 mg/g, about 65 mg/g, about 70 mg/g, about 75 mg/g, or about 80 mg/g of EPA or a pharmaceutically acceptable salt thereof In some embodiments, the natural source comprises at least or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than 95% of a compound of EPA or pharmaceutically acceptable salt thereof.
103271 In certain embodiments, in the treatment, prevention, or amelioration of one or more symptoms of the disorders, diseases, or conditions described herein, an appropriate dosage level of the compound of DHA or a pharmaceutically acceptable salt thereof generally is ranging from about 1 to 12000 mg, from about 1000 to 12000mg, about 2000 to 12000 mg, about 3000 to 12000 mg about 4000 to 12000 mg, about 5000 to 12000 mg, about 6000 to 12000 mg, about 1000 to 11000 mg, about 1000 to 10000 mg, about 1000 to 9000 mg, about 1000 to 8000 mg, or about 1000 to 7000 mg, which can be administered in single or multiple doses. In certain embodiments, the DHA or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000mg or any range derivable therein.
103281 In certain embodiments, the DHA, or pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 275 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000, about 1200, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, about 2400, about 2500, about 2600, about 2800, about 3000, about 4000, about 5000, about 6000, about 7000, about 8000 mg mg/day. 1000 to 12000mg, about 2000 to 12000 mg, about 3000 to 12000 mg about 4000 to 12000 mg, about 5000 to 12000 mg, about 6000 to 12000 mg, about 1000 to 11000 mg, about 1000 to 10000 mg, about 1000 to 9000 mg, about 1000 to 8000 mg, or about 1000 to 7000 mg, which can be administered in single or multiple doses. In certain embodiments, the DHA or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000mg or any range derivable therein.
[0329] For oral administration, the pharmaceutical compositions provided herein can be formulated in the form of tablets or capsules containing from about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about 5100 mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000mg of the compound of DHA or a pharmaceutically acceptable salt thereof for the symptomatic adjustment of the dosage to the patient to be treated.
103301 In some embodiments, the DHA, or pharmaceutically acceptable salt thereof is administered in an amount of about or at most about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg, about 5000 mg about MOO mg, about 5200 mg, about 5300 mg, about 5400 mg, about 5500 mg, about 5600 mg, about 5700 mg, about 5800 mg, about 5900 mg, about 6000 mg, about 6100 mg, about 6200 mg, about 6300 mg, about 6400 mg, about 6500 mg, about 6600 mg, about 6700 mg, about 6800 mg, about 6900 mg, about 7000 mg, about 7100 mg, about 7200 mg, about 7300 mg, about 7400 mg, about 7500 mg, about 7600 mg, about 7700 mg, about 7800 mg, about 7900 mg, about 8000 mg, about 8100 mg, about 8200 mg, about 8300 mg, about 8400 mg, about 8500 mg, about 8600 mg, about 8700 mg, about 8800 mg, about 8900 mg, about 9000 mg, about 9100 mg, about 9200 mg, about 9300 mg, about 9400 mg, about 9500 mg, about 9600 mg, about 9700 mg, about 9800 mg, about 9900 mg, or about 10000 mg, about 10100 mg, about 10200 mg, about 10300 mg, about 10400 mg, about 10500 mg, about 10600 mg, about 10700 mg, about 10800 mg, about 10900 mg, about 11000 mg about 11100 mg, about 11200 mg, about 11300 mg, about 11400 mg, about 11500 mg, about 11600 mg, about 11700 mg, about 11800 mg, about 11900 mg, or about 12000 mg or any range derivable therein. In some embodiments, the DHA is administered in a range of about 1000 to 12000 mg/day, about 2000 to 12000 mg/day, about 3000 to 12000 mg/day about 4000 to 12000 mg/day, about 5000 to 12000 mg/day, about 6000 to 12000 mg/day, about 1000 to 11000 mg/day, about 1000 to 10000 mg/day, about 1000 to 9000 mg/day, about 1000 to 8000 mg/day, or about 1000 to 7000 mg/day. In some embodiments, the DHA or pharmaceutically acceptable salt thereof is derived from a natural source such that about or at most about 1 mg/day, about 10 mg/day, about 50 mg/day, about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 800 mg/day, about 900 mg/day, about 1000 mg/day, about 1100 mg/day, about 1200 mg/day, about 1300 mg/day, about 1400 mg/day, about 1500 mg/day, about 1600 mg/day, about 1700 mg/day, about 1800 mg/day, about 1900 mg/day, about 2000 mg/day, about 2100 mg/day, about 2200 mg/day, about 2300 mg/day, about 2400 mg/day, about 2500 mg/day, about 2600 mg/day, about 2700 mg/day, about 2800 mg/day, about 2900 mg/day, about 3000 mg/day, about 3100 mg/day, about 3200 mg/day, about 3300 mg/day, about 3400 mg/day, about 3500 mg/day, about 3600 mg/day, about 3700 mg/day, about 3800 mg/day, about 3900 mg/day, about 4000 mg/day, about 4100 mg/day, about 4200 mg/day, about 4300 mg/day, about 4400 mg/day, about 4500 mg/day, about 4600 mg/day, about 4700 mg/day, about 4800 mg/day, about 4900 mg/day, about 5000 mg/day about 5100 mg/day, about 5200 mg/day, about 5300 mg/day, about 5400 mg/day, about 5500 mg/day, about 5600 mg/day, about 5700 mg/day, about 5800 mg/day, about 5900 mg/day, about 6000 mg/day, about 6100 mg/day, about 6200 mg/day, about 6300 mg/day, about 6400 mg/day, about 6500 mg/day, about 6600 mg/day, about 6700 mg/day, about 6800 mg/day, about 6900 mg/day, about 7000 mg/day, about 7100 mg/day, about 7200 mg/day, about 7300 mg/day, about 7400 mg/day, about 7500 mg/day, about 7600 mg/day, about 7700 mg/day, about 7800 mg/day, about 7900 mg/day, about 8000 mg/day, about 8100 mg/day, about 8200 mg/day, about 8300 mg/day, about 8400 mg/day, about 8500 mg/day, about 8600 mg/day, about 8700 mg/day, about 8800 mg/day, about 8900 mg/day, about 9000 mg/day, about 9100 mg/day, about 9200 mg/day, about 9300 mg/day, about 9400 mg/day, about 9500 mg/day, about 9600 mg/day, about 9700 mg/day, about 9800 mg/day, about 9900 mg/day, or about 10000 mg/day, about 10100 mg/day, about 10200 mg/day, about 10300 mg/day, about 10400 mg/day, about 10500 mg/day, about 10600 mg/day, about 10700 mg/day, about 10800 mg/day, about 10900 mg/day, about 11000 mg/day about 11100 mg/day, about 11200 mg/day, about 11300 mg/day, about 11400 mg/day, about 11500 mg/day, about 11600 mg/day, about 11700 mg/day, about 11800 mg/day, about 11900 mg/day, or about 12000mg/day DHA or pharmaceutically acceptable salt thereof is administered.
[0331] In some embodiments, the natural source comprises at least or about 1 mg/g, about 5 mg/g, about 10 mg/g, about 15 mg/g, about 20 mg/g, about 25 mg/g, about 30 mg/g, about 35 mg/g, about 40 mg/g, about 45 mg/g, about 50 mg/g, about 55 mg/g, about 60 mg/g, about 65 mg/g, about 70 mg/g, about 75 mg/g, or about 80 mg/g of DHA or a pharmaceutically acceptable salt thereof. In some embodiments, the natural source comprises at least or about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than 95% of a compound of DHA or pharmaceutically acceptable salt thereof.
[0332] In some embodiments, a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and a fatty acid are administered at a ratio of about 1:1, about 1:5, about 1:10, about 1:15, about 1:20, about 1:25, about 1:30, about 1:35, about 1:40, about 1:45, about 1:50, about 1:55, about 1:60, about 1:65, about 1:70, about 1:75, about 1:80, about 1:85, about 1:90, about 1:95, about 1:100, about 1:150, about 1:200, about 1:250, about 1:300, about 1:350, about 1:400, about 1:450, about 1:500, about 1:550, about 1:600, about 1:650, about 1:700, about 1:750, about 1:800, about 1:850, about 1:900, about 1:950, or about 1:1000. In some embodiments, a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and an oleic acid are administered at a ratio of about 1:1, about 1:5, about 1:10, about 1:15, about 1:20, about 1:25, about 1:30, about 1:35, about 1:40, about 1:45, about 1:50, about 1:55, about 1:60, about 1:65, about 1:70, about 1:75, about 1:80, about 1:85, about 1:90, about 1:95, about 1:100, about 1:150, about 1:200, about 1:250, about 1:300, about 1:350, about 1:400, about 1:450, about 1:500, about 1:550, about 1:600, about 1:650, about 1:700, about 1:750, about 1:800, about 1:850, about 1:900, about 1:950, or about 1:1000. In some embodiments, a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and a EPA are administered at a ratio of about 1:1, about 1:5, about 1:10, about 1:15, about 1:20, about 1:25, about 1:30, about 1:35, about 1:40, about 1:45, about 1:50, about 1:55, about 1:60, about 1:65, about 1:70, about 1:75, about 1:80, about 1:85, about 1:90, about 1:95, or about 1:100. In some embodiments, a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and a DHA are administered at a ratio of about 1:1, about 1:5, about 1:10, about 1:15, about 1:20, about 1:25, about 1:30, about 1:35, about 1:40, about 1:45, about 1:50, about 1:55, about 1:60, about 1:65, about 1:70, about 1:75, about 1:80, about 1:85, about 1:90, about 1:95, about 1:100, about 1:150, about 1:200, about 1:250, about 1:300, about 1:350, about 1:400, about 1:450, about 1:500, about 1:550, about 1:600, about 1:650, about 1:700, about 1:750, about 1:800, about 1:850, about 1:900, about 1:950, or about 1:1000. In some embodiments, the pharmaceutical compositions provided herein can be formulated in the form of an injection or I. V. infusion containing a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated in the form of an injection or I.V.
infusion containing oleic acid or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated in the form of an injection or I.V. infusion containing DHA or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated in the form of an injection or I.V. infusion containing EPA or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions provided herein can be formulated in the form of an injection or I.V.
infusion containing a compound of Formula (I); an oleic acid; EPA; DHA; a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof; or a combination thereof. The dose per day described herein may be given once per day or multiple times per day in the form of sub-doses given bid, t.i.d., q.i. d., or the like where the number of sub-doses equal the dose per day. The pharmaceutical compositions can be administered on a regimen of 1 to 4 times per day, including once, twice, three times, and four times per day. In some embodiments, the pharmaceutical compositions are administered once per day. In some embodiments, the pharmaceutical compositions are administered twice per day. In some embodiments, the pharmaceutical compositions are administered three times per day. In some embodiments, a loading dose, followed by maintenance doses, of the pharmaceutical compositions are administered.
[0333] In some embodiments, the pharmaceutical compositions provided herein are administered as a tablet. In some embodiments, the pharmaceutical compositions provided herein are administered as a capsule. In some embodiments, the pharmaceutical compositions provided herein are administered as an injection. In some embodiments, the pharmaceutical compositions provided herein are administered as an I.V. infusion.
[0334] In some embodiments, the pharmaceutical compositions provided herein are administered as an I.V. infusion over a period of about 15 minutes. In some embodiments, the pharmaceutical compositions provided herein are administered as an I.V. infusion over a period of about 30 minutes.
In some embodiments, the pharmaceutical compositions provided herein are administered as an I. V.
infusion over a period of about 45 minutes. In some embodiments, the pharmaceutical compositions provided herein are administered as an I.V. infusion over a period of about one hour. In some embodiments, the pharmaceutical compositions provided herein are administered as an I.V. infusion over a period of about two hours. In some embodiments, the pharmaceutical compositions provided herein are administered as an I.V. infusion over a period of about three hours or more.
[0335] In some embodiments, the pharmaceutical compositions provided herein are administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, or about 30 days.
[0336] In some embodiments, the pharmaceutical compositions provided herein are administered for administered daily, every other day, every other day 3 times a week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 3 days, every 4 days, every 5 days, every 6 days, weekly, bi-weekly, 3 times a week, 4 times a week, 5 times a week, 6 times a week, once a month, twice a month, 3 times a month, once every 2 months, once every 3 months, once every 4 months, once every months, or once every 6 months.
103371 In some instances, the method for the administration of multiple compounds (e.g., a compound of Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof) comprises administering compounds within 48 hours or less of each other. In some embodiments administration occurs within 24 hours, 12 hours, 6 hours, 3 hours, 1 hour, or 15 minutes. In some instances, the compounds are administered simultaneously. One example of simultaneous administration is the injection of one compound immediately before, after, or during the oral administration of the second compound, immediately referring to a time less than about 5 minutes.
[0338] In some embodiments of the pharmaceutical compositions described herein, a second dose is administered about 1 hour after the first dose, a second dose is administered about 2 hours after the first dose, a second dose is administered about 3 hours after the first dose, a second dose is administered about 4 hours after the first dose, a second dose is administered about 5 hours after the first dose_ a second dose is administered about 6 hours after the first dose, a second dose is administered about 7 hours after the first dose, a second dose is administered about 8 hours after the first dose, a second dose is administered about 9 hours after the first dose, a second dose is administered about 10 hours after the first dose, a second dose is administered about 11 hours after the first dose, or a second dose is administered about 12 hours after the first dose. In some embodiments of the pharmaceutical compositions described herein, the second dose is administered about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours after completion of administration of the first dose by I.V.
infusion. In some embodiments of the pharmaceutical compositions, the second dose is administered about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hours after initiation of administration of the first dose by IV. infusion.
Subjects [0339] In some embodiments, the subject is immunocompromised. In some embodiments, the subject is an immunocompromised human subject. In some embodiments, the human subject is under the age of 1 year. In some embodiments, the human subject is an infant under 1 month old. In some embodiments, the human subject is over the age of 70 years.
[0340] In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human.
[0341] It is frequently beneficial to improve one of more physical properties of the treatment modalities disclosed herein and/or the manner in which they are administered.
Improvements of physical properties include, for example, methods of increasing water solubility, bi availability, serum half-life, and/or therapeutic half-life; and/or modulating biological activity. Modifications known in the art include pegylation, Fc-fusion and albumin fusion. Although generally associated with large molecule agents (e.g., polypeptides), such modifications have recently been evaluated with particular small molecules. By way of example, Chiang, M. et al. (J. Am. Chem.
Soc., 2014, 136(9):3370-73) describe a small molecule agonist of the adenosine 2a receptor conjugated to the immunoglobulin Fc domain. The small molecule-Fc conjugate retained potent Fc receptor and adenosine 2a receptor interactions and showed superior properties compared to the unconjugated small molecule. Covalent attachment of PEG molecules to small molecule therapeutics has also been described (Li, W. et al., Progress in Polymer Science, 2013 38:421-44).
[0342] The compounds of the present disclosure may be administered to a subject in an amount that is dependent upon, for example, the goal of administration (e.g., the degree of resolution desired); the age, weight, sex, and health and physical condition of the subject to which the formulation is being administered; the route of administration; and the nature of the disease, disorder, condition or symptom thereof. The dosing regimen may also take into consideration the existence, nature, and extent of any adverse effects associated with the agent(s) being administered.
Effective dosage amounts and dosage regimens can readily be determined from, for example, safety and dose-escalation trials, in vivo studies (e.g., animal models), and other methods known to the skilled artisan.
[0343] In general, dosing parameters dictate that the dosage amount be less than an amount that could be irreversibly toxic to the subject (the maximum tolerated dose (MTD)) and not less than an amount required to produce a measurable effect on the subject. Such amounts are determined by, for example, the pharmacokinetic and pharmacodynamic parameters associated with ADME, taking into consideration the route of administration and other factors.
[0344] An effective dose (ED) is the dose or amount of an agent that produces a therapeutic response or desired effect in some fraction of the subjects taking it. The -median effective dose- or ED50 of an agent is the dose or amount of an agent that produces a therapeutic response or desired effect in 50%
of the population to which it is administered. Although the ED50 is commonly used as a measure of reasonable expectance of an agent's effect, it is not necessarily the dose that a clinician might deem appropriate taking into consideration all relevant factors. Thus, in some situations the effective amount is more than the calculated ED50, in other situations the effective amount is less than the calculated ED50, and in still other situations the effective amount is the same as the calculated ED50.
[0345] In addition, an effective dose of the compounds of the present disclosure may be an amount that, when administered in one or more doses to a subject, produces a desired result relative to a healthy subject. For example, for a subject experiencing a particular disorder, an effective dose may be one that improves a diagnostic parameter, measure, marker and the like of that disorder by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, where 100% is defined as the diagnostic parameter, measure, marker and the like exhibited by a normal subject.
[0346] In embodiments, the dosage of the desired compound is contained in a -unit dosage form."
The phrase "unit dosage form" refers to physically discrete units, each unit including a predetermined amount of the compound (e.g., a compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof), sufficient to produce the desired effect. It will be appreciated that the parameters of a unit dosage form will depend on the particular agent and the effect to be achieved.
NUMBERED EMBODIMENTS
[0347] Numbered embodiment 1 comprises a composition, comprising: (i) a compound of structural Formula (I):
R1)n2 n1 0 n3 (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
R' is independently hydrogen, halogen, ¨OR'-, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted C1-6 alkyl; and RIP' is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and (ii) a fatty acid, wherein a ratio of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and the fatty acid is in a range of about 1:5 to about 1:1000.
Numbered embodiment 2 comprises a composition of numbered embodiment 1, wherein the compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 0.1%(w/v) to about 50% (w/v). Numbered embodiment 3 comprises a composition of any one of numbered embodiments 1-2, the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 10% (w/v). Numbered embodiment 4 comprises a composition of any one of numbered embodiments 1-3, wherein the compound of Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of less than about 2% (w/v). Numbered embodiment 5 comprises a composition of any one of numbered embodiments 1-4, wherein the fatty acid is a cannabinoid.
Numbered embodiment 6 comprises a composition of any one of numbered embodiments 1-5, wherein the fatty acid is a polyunsaturated fatly acid (PUFA). Numbered embodiment 7 comprises a composition of any one of numbered embodiments 1-6, wherein the PUFA is anandamide.
Numbered embodiment 8 comprises a composition of any one of numbered embodiments 1-7, wherein the PUFA is a cannabinoid. Numbered embodiment 9 comprises a composition of any one of numbered embodiments 1-8, wherein the PUFA is a n-3 PUFA. Numbered embodiment 10 comprises a composition of any one of numbered embodiments 1-9, wherein the PUFA is a n-6 PUFA. Numbered embodiment 11 comprises a composition of any one of numbered embodiments 1-10, wherein the fatty acid is an omega-3 fatty acid. Numbered embodiment 12 comprises a composition of any one of numbered embodiments 1-11, wherein the omega-3 fatty acid is DHA
(docosahexaenoic acid), EPA (eicosapentaenoic acid), LNA (linolenic acid), or combinations thereof.
Numbered embodiment 13 comprises a composition of any one of numbered embodiments 1-12, wherein the omega-3 fatty acid is DHA (docosahexaenoic acid), EPA
(eicosapentaenoic acid), LNA
(linolenic acid), or combinations thereof. Numbered embodiment 14 comprises a composition of any one of numbered embodiments 1-13, wherein the fatty acid is oleic acid or erucic acid. Numbered embodiment 15 comprises a composition of any one of numbered embodiments 1-14, wherein a ratio of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and the fatty acid is in a range of about 1:20 to about 1:100.
Numbered embodiment 16 comprises a composition of any one of numbered embodiments 1-15, wherein a ratio of the compound of Formula (1) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and the fatty acid is about 1:60. Numbered embodiment 17 comprises a composition of any one of numbered embodiments 1-16, wherein the composition is in a form for oral dosing or administration.
Numbered embodiment 18 comprises a composition of any one of numbered embodiments 1-17, wherein the compound of structural Formula (I) has structural Formula (I-A):
R1=1 n1 0 n3 (I-A), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
R" is hydrogen, halogen, ¨ORIJA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
10.2 is hydrogen, halogen, ¨0RI.2A, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and R1.1A and R1.2A are independently hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONHI, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
Numbered embodiment 19 comprises a composition of any one of numbered embodiments 1-18, wherein:
R" is CH3; and R1.2 is OH.
Numbered embodiment 20 comprises a composition of any one of numbered embodiments 1-19, wherein X is 0. Numbered embodiment 21 comprises a composition of any one of numbered embodiments 1-20, wherein X is NH. Numbered embodiment 22 comprises a composition of any one of numbered embodiments 1-21, wherein is a double bond. Numbered embodiment 23 a comprises a composition of any one of numbered embodiments 1-22, wherein = is a single bond.
Numbered embodiment 24 comprises a composition of any one of numbered embodiments 1-23, wherein n1 is 2. Numbered embodiment 25 comprises a composition of any one of numbered embodiments 1-24, wherein n1 is 1. Numbered embodiment 26 comprises a composition of any one of numbered embodiments 1-25, wherein n1 is 0. Numbered embodiment 27 comprises a composition of any one of numbered embodiments 1-26, wherein R2 is unsubstituted alkyl.
Numbered embodiment 28 comprises a composition of any one of numbered embodiments 1-27, wherein R2 is ¨CH(CH3)2 or ¨CH3. Numbered embodiment 29 comprises a composition of any one of numbered embodiments 1-28, wherein the compound is at least one of:
HO HO Si HO HO
HO HO
HO HO
HO
HO is , or HO
0 =
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
Numbered embodiment 30 comprises a composition of any one of numbered embodiments 1-29, HO
wherein the compound is: 0 or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof Numbered embodiment 31 comprises a composition of any one of numbered embodiments 1-30, wherein the compound of structural Formula (I) is capsaicin. Numbered embodiment 32 comprises a composition of any one of numbered embodiments 1-31, wherein the compound of structural Formula (1) is dihydrocapsaicin. Numbered embodiment 33 comprises a method of treating or preventing a capsaicin-responsive disease or disorder, comprising administering to a subject in need thereof the composition of any one of numbered embodiments 1-32. Numbered embodiment 34 comprises a method of any one of numbered embodiments 1-33, wherein the disease or disorder is a cell proliferative disease, obesity, diabetes, a bacterial infection, a cardiovascular disease, a neurodegenerative disease or disorder, an inflammatory disease or disorder, a comorbidity, an autoimmune disease, hypercholesterolemia or a mood disorder. Numbered embodiment 35 comprises a method of any one of numbered embodiments 1-34, wherein the mood disorder is depression. Numbered embodiment 36 comprises a method of any one of numbered embodiments 1-35, wherein the inflammatory disease or disorder is rheumatoid arthritis.
Numbered embodiment 37 comprises a method of any one of numbered embodiments 1-36, wherein the cell proliferative disease is a cancer. Numbered embodiment 38 comprises a method of any one of numbered embodiments 1-36, wherein the disorder is diabetes or obesity. Numbered embodiment 39 comprises a method of any one of numbered embodiments 1-38, wherein the comorbidity is chronic kidney disease, stroke, congestive heart failure, dementia, schizophrenia, hepatitis, autism spectrum disorder, HIV, or a combination thereof. Numbered embodiment 40 comprises a method of any one of numbered embodiments 1-39, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally.
Numbered embodiment 41 comprises a method of any one of numbered embodiments 1-40, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally via a suspension or solution. Numbered embodiment 42 comprises a method of any one of numbered embodiments 1-41, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally via a solid dosage form. Numbered embodiment 43 comprises a method of any one of numbered embodiments 1-42, wherein the form is a tablet or capsule. Numbered embodiment 44 comprises a method of any one of numbered embodiments 1-43, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by inhalation, nebulization, or nasal delivery. Numbered embodiment 45 comprises a method of any one of numbered embodiments 1-44, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by inhalation via a vaporizer. Numbered embodiment 46 comprises a method of any one of numbered embodiments 1-45, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered parenterally. Numbered embodiment 47 comprises a method of any one of numbered embodiments 1-46, the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered via parenteral injection, infusion, or implantation. Numbered embodiment 48 comprises a method of any one of numbered embodiments 1-47, wherein the parenteral injection is intravenous, intramuscular, subcutaneous, or intradermal. Numbered embodiment 49 comprises a method of any one of numbered embodiments 1-48, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered via a suppository. Numbered embodiment 50 comprises a method of any one of numbered embodiments 1-49, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered cutaneous or transdermal delivery. Numbered embodiment 51 comprises a method of any one of numbered embodiments 1-50, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by sublingual or buccal delivery. Numbered embodiment 52 comprises a method of any one of numbered embodiments 1-51, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the fatty acid are administered simultaneously, approximately simultaneously, or sequentially, in any order. Numbered embodiment 53 comprises a method of any one of numbered embodiments 1-52, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the fatty acid are administered simultaneously or approximately simultaneously. Numbered embodiment 54 comprises a method of any one of numbered embodiments 1-53, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the fatty acid are administered sequentially. Numbered embodiment 55 comprises a method of any one of numbered embodiments 1-54, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is released before the fatty acid.
Numbered embodiment 56 comprises a method of any one of numbered embodiments 1-55, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is released after the fatty acid.
EXAMPLES
Example 1: Effects of fatty acids on tolerance to capsaicinoids (capsaicin or dihydrocapsaicin) in C57BL/63Itj mice [0348] The ability of oleic acid (OA) and eicosapentanenoic acid (EPA) to prevent capsacinoid-induced intolerance was assessed in 42-week old male C57BL/6.11kj mice. Mice were randomized to the following five groups (n=12/group): (1) Vehicle control (615 mg/Kg body weight cottonseed oil);
(2) Capsaicin + OA (10 mg/kg capsaicin + 615 mg/kg oleic acid); (3) Capsaicin + EPA (10 mg/kg capsaicin + 615 mg/kg EPA); (4) Dihy drocapsaicin + OA (2 mg/kg dihydrocapsaicin + 615 mg/kg oleic acid); and (5) Dihydrocapsaicin + EPA (2 mg/kg dihydrocapsaicin + 615 mg/kg EPA). The human equivalent doses of capsaicin and dihydrocapsaicin were calculated via allometric scaling to be 114 mg/day and 26 mg/day, respectively. Animals were administered the formulations via oral gavage in a volume of 5 mL/kg) twice daily for 42 days. Food intake was measured daily for the first 14-days, and the following clinical signs of distress or discomfort were assessed daily throughout the study: Unusual aggression, change in appetite or feeding behavior, change in activity/restlessness, decrease in grooming, excessive licking and scratching/self-mutilation, abnormal stance/hunched posture, rapid respiration. There was no significant among groups for food and/or water intake (Fig.
1), indicating that the inclusion of OA or EPA suppressed the commonly observed alterations in appetite with capsaicinoid administration.
[0349] The administration of all substances was well-tolerated and equally tolerated among groups, with no clinical signs of distress evident in any animal from the first dose (dose 1, day 1) to the final dose (dose 84, day 42).
Example 2: Effects of Capsaicinoid-EPA Combinations on Hepatic Outcomes in a Mouse Model of Diet-Induced Obesity and Non-Alcoholic Steatosis (NASH) [0350] Five-week old male C57BL/6Rj mice were fed a high fat (40%) containing 20% fructose and 2% cholesterol for 37 weeks to induce modest obesity and NASH. They were then randomized to the following three groups (n=12/group) using magnetic resonance imaging (MRI) of body fat to ensure equivalent adiposity across groups: (1) Vehicle control (615 mg/Kg body weight cottonseed oil); (2) Capsaicin (Cap) + EPA (10 mg/kg cap + 615 mg/kg EPA); and (3) DHC + EPA (2 mg/kg DHC + 615 mg/kg EPA). Animals were administered the formulations via oral gavage in a volume of 5 mL/kg) twice daily for 42 days. At the conclusion of the study animals were fasted for four hours and then terminated and the livers removed, weighed, and biopsied for steatosis via quantitative hematoxylin and eosin (H&E) staining, inflammation via immunohistochemistry (IHC) for Galectin-3 (Gal-3), stellate cell activation via IHC for a-smooth muscle actin (a-SMA) and fibrosis via IHC for collagen (Collal). Treatment with either Capsaicin-EPA or DHC-EPA resulted in a significant decrease in hepatic steatosis (Fig. 2), and in stellate cell activation (a-SMA; Fig. 3).
There was a trend towards decreasing fibrosis (Collal), but Collal changes were not statistically significant (Fig. 4). However, changes in fibrosis generally take longer to manifest (>12 weeks, vs. the 6-week duration of this study).
103511 There were no significant effects or trends evident for Gal-3. These data demonstrate that capsaicinoid-EPA combinations significantly reverse diet-induced steatosis and stellate cell activation in this mouse model of NASH. The effects on stellate cell activation indicate an anti-fibrotic effect that will manifest as reduced collagen (Col lad) over longer periods of treatment.
Example 3. Effects of Capsaicinoid-OA Combinations on Body Weight and Adiposity in a Mouse Model of Diet-Induced Obesity [0352] Five-week old male C57BL/6Rj mice were fed a high fat (40%) containing 20% fructose and 2% cholesterol for 37 weeks to induce modest obesity. They were then randomized to the following three groups (n=12/group) using magnetic resonance imaging (MRI) of body fat to ensure equivalent adiposity across groups: (1) Vehicle control (615 mg/Kg body weight cottonseed oil); (2) Capsaicin (Cap) + OA (10 mg/kg cap + 615 mg/kg OA); and (3) DHC + OA (2 mg/kg DHC + 615 mg/kg OA).
Animals were administered the formulations via oral gavage in a volume of 5 mL/kg) twice daily for 42 days. Body weight was measured daily, and adiposity (body fat mass) was measured via MRI at study conclusion. DHC+0A reduced body weight compared to vehicle control (Fig.
5). This effect was evident by day 5 and persisted throughout the 42-day study. Cap-OA exerted no effect on weight. This was reflected in a significant decrease in body fat in the DHC+0A
group and a corresponding decrease in body fat as a percentage of body weight at the conclusion of the study (Fig. 6).
[0353] These data indicate that DHC-0A, but not Cap-OA, exerts an anti-obesity effect in this animal model of obesity.
Example 4. Effects of capsaicinoid-fatty acid combinations on glucose tolerance and insulin sensitivity in diabetic mice.
[0354] Eighty-four male db/db mice (BKS. CG-Dock7m+/+LeprdbJ) are randomized at 8 weeks of age to produce seven equivalent groups (n=12/group) with respect to 4-hour fasting glucose and body weight. Treatment groups are as follow: Control (untreated); Capsaicin (5 mg/kg)+0A (615 mg/kg);
DHC (1 mg/kg)+0A (615 mg/kg); capsaicin (10 mg/kg)+0A (615 mg/kg); DHC (10 mg/kg)+0A
(615 mg/kg); capsaicin (5 mg/kg); DHC (1 mg/kg). Animals are administered the formulations via oral gavage in a volume of 5 mL/kg) twice daily for 28 days. Blood glucose is measured following a four hour fast on days 0,7, 14, 21 and 28. On day 28, an oral glucose tolerance test (OG I 1) is performed following a four-hour fast. Glucose (1.2 g/kg) is dosed at t=10 minutes, and glucose and insulin are measured at t=-60 minutes, 0, 15, 30, 60, 120, 180 and 240 minutes.
[0355] Fasting glucose is 300 mg/dL in the control group and is dose-responsively decreased to 200 mg/dL by both the capsaicin+0A and DHC+0A treatments. This is effect is evident within 7 days of treatment and is maintained throughout the rest of the study, and there is no significant difference between the capsaicin+0A and DHC+0A combinations Area under the glucose curve for the OGTT
is dose-responsively decreased by 50%, and area under the insulin response curve during OGTT is dose-responsively decreased by 60% by the capsaicinoid-fatty acid combinations, with no significant difference between the capsaicin+0A and DHC+0A combinations. Capsaicin and DHC
administered in the absence of OA are poorly tolerated and the animals do not adapt during the first 72 hours (6 doses); consequently, these two groups are discontinued for animal welfare reasons.
Example 5. Fatty acid modulators reduce capsacinoid-induced TRPV1 signaling in vitro.
103561 The aim of this study was to evaluate the effects of oleic acid on antagaonizing capsaicinoid-induced TRPV1 primary signaling in Human dorsal root ganglia (DRG) neurons in culture. Human DRG neurons were studied in a perfusion system using the calcium dye Fluo-8.
Detection of intracellular calcium transients was accomplished by measuring the changes in the fluorescence intensity of the Fluo-8 calcium indicator upon excitation at 480 nm and recording of the emitted signal at 520 nm using a pcoEDGE sCMOS camera mounted on an inverted microscope (Olympus IX71). The following protocol was utilized to study the effects of the fatty acids on capsaicin and DHC-stimulated calcium currents.
Table 1: Protocol for study Acquisition Application Sequence Rate 1 image every Vehicle (Baseline) 30sec recorded 15sec 1 image every Vehicle (control) or OA (5min) 4.5min recorded 15sec Agonist First Application Sequence 1 image every Baseline with Vehicle or OA 30sec recorded 5sec Agonist (capsaicin or DHC) 1 image every 30sec recorded 1/2 5sec 1 image every Washout 4min recorded 5sec 1 image every Washout 10min recorded 15sec [0357] Treatment with capsaicin alone resulted in 74% of the treated neurons responding, and this figure was reduced to 51% by oleic acid administration. Treatment with DHC
alone resulted in 59%
of the neurons responding, and this figure was reduced to 38% by oleic acid administration, with a corresponding reduction in maximal calcium (AF/F0) signal from 4.57 to 2.81.
103581 Calcium imaging over time is shown in Figs. 7A-7D. These data indicate significant attenuation of TRPV1 signaling by oleic acid.
Example 6: The effect of capsaicin and a TrpV1 inhibitor on Resting Metabolic Weight.
103591 Detailed Description: This study is a double-blind, placebo-controlled, single center, randomized, parallel arm clinical trial to test the impact of capsaicin and a TrpV1 inhibitor as described below ingested for 4 weeks on resting metabolic rate and fat oxidation measured by indirect calorimetry.
Primary Outcome The consumption of capsaicin and a TrpV1 inhibitor will significantly increase resting Measures energy expenditure and fat oxidation [ Time Frame: 4 weeks ].
Descriptive Information A 4 week intake of drug combination to find a natural substance that may modify Brief Title energy balance and may enhance health in combination with lifestyle changes with possible decrease in body weight.
Effect of 4-week Capsaicin and a TrpV1 Inhibitor Ingestion on Resting Metabolic Official Title Rate: A Double-blind Randomized Parallel Arm Study A 4 week intake of drug to find a natural substance that may modify energy balance Brief Summary and may enhance health in combination with lifestyle changes with possible decrease in body weight Study Type Interventional Study Phase Phase 2 Allocation: Randomized Intervention Model: Parallel Assignment Study Design Masking: Double (Participant, Investigator) Primary Purpose: Prevention Condition Obesity, Weight = Other: Capsaicin in combination a TrpV1 inhibitor (EPA or oleic acid) Intervention = Capsules will contain 0.1%, 1%, or 10% (w/v) capsaicin and a TrpV1 inhibitor in a range of about 1:5 to about 1:1000.
= Placebo Comparator: Sugar pill (Placebo 0 mg/d) 0 mg/d sugar pill Study Arms Intervention: Other: Capsaicin and TrpV1 inhibitor combination = Active Comparator: Capsaicin and TrpV1 combination (EPA) Drug 0.1% (w/v) including Placebo Intervention: Other: Capsaicin and TrpV1 inhibitor combination = Active Comparator: 1% (w/v) capsaicin and a TrpV1 inhibitor (EPA) Drug 1% (w/v) including Placebo Intervention: Other: capsaicin and a TrpV1 inhibitor combination = Active Comparator: Capsaicin and TrpV1 combination (EPA) Drug 10% (w/v) including Placebo Intervention: Other: Capsaicin and TrpV1 inhibitor combination = Active Comparator: Capsaicin and TrpV1 combination (oleic acid) Drug 0.1% (w/v) including Placebo Intervention: Other: Capsaicin and TrpV1 inhibitor combination = Active Comparator: 1% (w/v) capsaicin and a TrpV1 inhibitor (oleic acid) Drug 1% (w/v) including Placebo Intervention: Other: capsaicin and a TrpV1 inhibitor combination = Active Comparator: Capsaicin and TrpV1 combination (oleic acid) Drug 10% (w/v) including Placebo Intervention: Other: Capsaicin and TrpV1 inhibitor combination Recruitment Information Inclusion Criteria:
= Men between 20-60 years old = Healthy as assessed by medical history and standard medical exam = Weight-stable = Body mass index of 25 to 34.9 kg/m2 = Non-smoker = Sedentary lifestyle: not being physically active greater than 3 days/week for 20 min each time for the previous 6 months, and not participating in regular resistance exercise.
Eligibility Exclusion Criteria:
Criteria = Subjects enrolled in a diet to increase or decrease body weight = Special diet or food aversions to common foods = Has allergy to chili pepper = Eating chili peppers on a daily basis = Usually consuming more than 2 cups of tea or coffee/day = Usually consuming more than 4 cans of caffeinated soft drinks a day = Usually consuming more than 3 standard alcohol drinks/day = Regular use of medications (weight loss drugs, drugs affecting energy metabolism, drugs for depression) ...................... ......................... .............................
............ ............ ................ ............ ............
............................. ............ ............
............................. ............ ........
= Usual intake of illicit substances = Claustrophobia = Participating or having participated in another clinical trial during the last 4 weeks prior to the beginning of this study Sex/Gender Sexes Eligible for Study: All Ages 20 years to 60 years (Adult, Older Adult) Accepts Healthy Yes Volunteers Outcome Respiratory calorimetry on days 0, 7 and 28 of the intervention to assess energy expenditure and respiratory quotient/substrate oxidation under fasting conditions Measurement (resting energy expenditure) and one-hour following a standardized meal.
[0360] Although the disclosure has been described with reference to the above example, it will be understood that modifications and variations are encompassed within the spirit and scope of the disclosure. Accordingly, the disclosure is limited only by the following claims.
Claims (56)
1. A composition, comprising:
(i) a compound of structural Formula (I):
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
It' is independently hydrogen, halogen, ¨ORIA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted CI-6 alkyl; and R1A is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨CI3,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and (ii) a fatty acid, wherein a ratio of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and the fatty acid is in a range of about 1:5 to about 1:1000.
(i) a compound of structural Formula (I):
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
a = is a single bond or double bond;
n1 and n2 are independently an integer from 0 to 2;
n3 is 0 or 1;
X is 0, NH, or S;
It' is independently hydrogen, halogen, ¨ORIA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
R2 is hydrogen or substituted or unsubstituted CI-6 alkyl; and R1A is hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨CI3,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and (ii) a fatty acid, wherein a ratio of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and the fatty acid is in a range of about 1:5 to about 1:1000.
2. The composition of claim 1, wherein the compound of structural Formula (I), or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of from about 0.1%(w/v) to about 50%
(w/v).
(w/v).
3. The composition of claim 1, wherein the compound of Formula (I), or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 10% (w/v).
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of greater than about 10% (w/v).
4. The composition of claim 1, wherein the compound of Formula (I), or an isotopic variant thereof;
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of less than about 2% (w/v).
or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof is present in the composition in an amount of less than about 2% (w/v).
5. The composition of claim 1, wherein the fatty acid is a cannabinoid.
6. The composition of claim 1, wherein the fatty acid is a polyunsaturated fatty acid (PUFA).
7. The composition of claim 6, wherein the PUFA is anandamide.
8. The composition of claim 6, wherein the PUFA is a cannabinoid.
9. The composition of claim 6, wherein the PUFA is a n-3 PUFA.
10. The composition of claim 6, wherein the PUFA is a n-6 P UFA.
11. The composition of claim 1, wherein the fatty acid is an omega-3 fatty acid.
12. The composition of claim 11, wherein the omega-3 fatty acid is DHA
(docosahexaenoic acid), EPA (eicosapentaenoic acid), LNA (linolenic acid), or combinations thereof
(docosahexaenoic acid), EPA (eicosapentaenoic acid), LNA (linolenic acid), or combinations thereof
13. The composition of claim 11, wherein the omega-3 fatty acid is DHA
(docosahexaenoic acid), EPA (eicosapentaenoic acid), LNA (linolenic acid), or combinations thereof
(docosahexaenoic acid), EPA (eicosapentaenoic acid), LNA (linolenic acid), or combinations thereof
14. The composition of claim 1, wherein the fatty acid is oleic acid or erucic acid.
15. The composition of claim 1, wherein a ratio of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and the fatty acid is in a range of about 1:20 to about 1:100.
16. The composition of claim 1, wherein a ratio of the compound of Formula (I) or a hydrate, solvate, tautomer, or pharmaceutically acceptable salt thereof and the fatty acid is about 1:60.
17. The composition of any one of claims 1-16, wherein the composition is in a form for oral dosing or administration.
18. The composition of any one of claims 1-17, wherein the compound of structural Formula (I) has structural Formula (I-A):
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
R" is hydrogen, halogen, ¨ORLIA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
T.1.2 I( is hydrogen, halogen, ¨0R1.24, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and R' 'A and R' 2A are independently hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein:
R" is hydrogen, halogen, ¨ORLIA, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl;
T.1.2 I( is hydrogen, halogen, ¨0R1.24, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and R' 'A and R' 2A are independently hydrogen, ¨CF3, ¨CC13, ¨CBr3, ¨C13,¨COOH, ¨CONH2, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
19. The pharmaceutical composition of claim 17, wherein:
R" is CH3; and R1.2 is OH.
R" is CH3; and R1.2 is OH.
20. The composition of claim 17, wherein X is O.
21. The composition of claim 17, wherein X is NH.
a
a
22. The composition of any one of claims 17-21, wherein = is a double bond.
a
a
23. The composition of any one of claims 17-21, wherein = is a single bond.
24. The composition of any one of claims 17-23, wherein n1 is 2.
25. The composition of any one of claims 17-23, wherein n1 is 1.
26. The composition of any one of claims 17-23, wherein n1 is O.
27. The composition of any one of claims 17-26, wherein R2 is unsubstituted alkyl.
28. The composition of any one of claims 17-27, wherein R2 is ¨CH(CH3)2 or ¨CH3.
29. The composition of claim 1, wherein the compound is at least one of:
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof.
30. The composition of claim 1, wherein the compound is:
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof
or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof
31. The composition of claim 1, wherein the compound of structural Formula (I) is capsaicin.
32. The composition of claim 1, wherein the compound of structural Formula (I) is dihydrocapsaicin.
33. A method of treating or preventing a capsaicin-responsive disease or disorder, comprising administering to a subject in need thereof the composition of any one of claims 1-32.
34. The method of claim 31, wherein the disease or disorder is a cell proliferative disease, obesity, diabetes, a bacterial infection, a cardiovascular disease, a neurodegenerative disease or disorder, an inflammatory disease or disorder, a comorbidity, an autoimmune disease, hypercholesterolemia or a mood disorder.
35. The method of claim 34, wherein the mood disorder is depression.
36. The method of claim 34, wherein the inflammatory disease or disorder is rheumatoid arthritis.
37. The method of claim 34, wherein the cell proliferative disease is a cancer.
38. The method of claim 34, wherein the disorder is diabetes or obesity.
39. The method of claim 34, wherein the comorbidity is chronic kidney disease, stroke, congestive heart failure, dementia, schizophrenia, hepatitis, autism spectrum disorder, HIV, or a combination thereof.
40. The method of any one of claims 31-39, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally.
41. The method of any one of claims 31-39, wherein the compound of structural Formula (1) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally via a suspension or solution.
42. The method of any one of claims 31-39, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally via a solid dosage form.
43. The method of claim 42, wherein the form is a tablet or capsule.
44. The method of any one of claims 31-39, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by inhalation, nebulization, or nasal delivery.
45. The method of claim 44, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by inhalation via a vaporizer.
46. The method of any one of claims 31-39, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered parenterally.
47. The method of any one of claims 31-39, wherein the compound of structural Formula (1) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered via parenteral injection, infusion, or implantation.
48. The method of claim 47, wherein the parenteral injection is intravenous, intramuscular, subcutaneous, or intradermal.
49. The method of any one of claims 31-39, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered via a suppository.
50. The method of any one of claims 31-39, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered cutaneous or transdermal delivery.
51. The method of any one of claims 31-39, wherein the compound of structural Formula (I) or an isotopic variant thereof; or a metabolite, pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered by sublingual or buccal delivery.
52. The method of any one of claims 31-39, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the fatty acid are administered simultaneously, approximately simultaneously, or sequentially, in any order.
53. The method of claim 52, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the fatty acid are administered simultaneously or approximately simultaneously.
54. The method of claim 52, wherein the compound of Formula (1), or a pharmaceutically acceptable salt thereof, and the fatty acid are administered sequentially.
55. The method of claim 52, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is released before the fatty acid.
56. The method of claim 52, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is released after the fatty acid.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202063126467P | 2020-12-16 | 2020-12-16 | |
US63/126,467 | 2020-12-16 | ||
PCT/US2021/063523 WO2022132902A1 (en) | 2020-12-16 | 2021-12-15 | Capsaicin and trpv1 modulator compositions and methods of use thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CA3224064A1 true CA3224064A1 (en) | 2022-06-23 |
Family
ID=82058619
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA3224064A Pending CA3224064A1 (en) | 2020-12-16 | 2021-12-15 | Capsaicin and trpv1 modulator compositions and methods of use thereof |
Country Status (2)
Country | Link |
---|---|
CA (1) | CA3224064A1 (en) |
WO (1) | WO2022132902A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115282134B (en) * | 2022-07-20 | 2023-06-23 | 天津中医药大学 | Application of capsaicin in preparation of medicine for treating fragile X syndrome |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5634984A (en) * | 1993-12-22 | 1997-06-03 | Union Oil Company Of California | Method for cleaning an oil-coated substrate |
US20100099766A1 (en) * | 2008-10-16 | 2010-04-22 | Novartis Ag | Topical NSAID compositions having sensate component |
MX2012011671A (en) * | 2010-04-09 | 2012-12-17 | Dsm Ip Assets Bv | Thermally stable oil-in-water emulsions containing an oil that contains polyunsaturated fatty acids. |
US20120199061A1 (en) * | 2011-02-04 | 2012-08-09 | The Hitt Companies | Method and apparatus for enhancing live-scan fingerprint reader images |
CA3143042A1 (en) * | 2019-06-11 | 2020-12-17 | Pano Therapeutics, Inc. | Capsaicin and trpv1 modulator combinations and methods of use thereof |
-
2021
- 2021-12-15 CA CA3224064A patent/CA3224064A1/en active Pending
- 2021-12-15 WO PCT/US2021/063523 patent/WO2022132902A1/en active Application Filing
Also Published As
Publication number | Publication date |
---|---|
WO2022132902A1 (en) | 2022-06-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20110015154A1 (en) | Supporting acetylcholine function | |
US20220098143A1 (en) | Capsaicin and trpv1 modulator combinations and methods of use thereof | |
PT1505973E (en) | Combinations for treating multiple myeloma | |
KR101909433B1 (en) | Agent for reducing adverse side effects of kinase inhibitor | |
BR112015023747B1 (en) | USE OF A STEROID CATION ANTIMICROBIAL COMPOUND (CSA) FOR THE PREPARATION OF A COMPOSITION TO TREAT, REDUCE, OR PREVENT ACUTE OR CHRONIC INFLAMMATION AND/OR ACUTE OR CHRONIC PAIN ASSOCIATED WITH A DISEASE OR A SYMPTOM OF DISEASE | |
RU2453303C1 (en) | Pharmaceutical composition for atopic dermatitis | |
CN110996949A (en) | Methods for treating behavioral changes | |
US20120208883A1 (en) | Treatment of oncological diseases | |
CA3224064A1 (en) | Capsaicin and trpv1 modulator compositions and methods of use thereof | |
ES2698363T3 (en) | Compositions of oxprenolol to treat cancer | |
CA3039767C (en) | Compositions and methods for treatment, amelioration, and prevention of anesthesia-induced hypothermia | |
WO2020047518A1 (en) | Ire1 kinase inhibitors and uses thereof | |
US10682343B2 (en) | Snoring treatment | |
ES2669248T3 (en) | Pharmaceutical combinations | |
US20240216304A1 (en) | Capsaicin and trpv1 modulator compositions and methods of use thereof | |
Arbi et al. | Intravenous dexamethasone in combination with caudal block prolongs postoperative analgesia in pediatric daycare surgery | |
CA2552759A1 (en) | Combination of organic compounds | |
US10221171B2 (en) | Oxathiazole thiazolium Hsp 70 inhibitors | |
CN104968340A (en) | Uses and methods for the treatment of liver diseases or conditions | |
WO2017148129A1 (en) | Pharmaceutical composition for treating cachexia and use thereof | |
TW202333729A (en) | Combinations | |
AU2007325797B2 (en) | Use of indolyl-3-glyoxylic acid derivatives including indibulin, alone or in combination with further agents for treating cancer | |
JP2022526755A (en) | Treatment of Attention Deficit Hyperactivity Disorder Using KDM1A Inhibitors such as Compound Bafidemstat | |
WO2010087150A1 (en) | Gastric acid secretion inhibitor, and potassium channel inhibitor | |
JP2022525679A (en) | How to Treat Borderline Personality Disorder |